MACC1

Gene Summary

Gene:MACC1; metastasis associated in colon cancer 1
Aliases: 7A5, SH3BP4L
Location:7p21.1
Summary:MACC1 is a key regulator of the hepatocyte growth factor (HGF; MIM 142409)-HGF receptor (HGFR, or MET; MIM 164860) pathway, which is involved in cellular growth, epithelial-mesenchymal transition, angiogenesis, cell motility, invasiveness, and metastasis. Expression of MACC1 in colon cancer (MIM 114500) specimens is an independent prognostic indicator for metastasis formation and metastasis-free survival (Stein et al., 2009 [PubMed 19098908]).[supplied by OMIM, Mar 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:metastasis-associated in colon cancer protein 1
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MACC1 (cancer-related)

Hu H, Tian D, Chen T, et al.
Metastasis-associated in colon cancer 1 is a novel survival-related biomarker for human patients with renal pelvis carcinoma.
PLoS One. 2014; 9(6):e100161 [PubMed] Free Access to Full Article Related Publications
Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease.

Muendlein A, Hubalek M, Geller-Rhomberg S, et al.
Significant survival impact of MACC1 polymorphisms in HER2 positive breast cancer patients.
Eur J Cancer. 2014; 50(12):2134-41 [PubMed] Related Publications
BACKGROUND: Deregulation of hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) signalling has been associated with poor clinical outcome in breast cancer and other cancers. The recently discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Potential links between genetic variants of the MACC1 gene and survival in breast cancer patients are unknown. In the present study, we therefore aimed to investigate the influence of MACC1 polymorphisms on event-free and overall survival in patients with human epidermal growth factor 2 (HER2)-positive breast cancer.
METHODS: The present study included 164 consecutive white patients with HER2-positive breast cancer. Three MACC1 polymorphisms, rs1990172, rs975263 and rs3735615, already associated with cancer prognosis or with potential functional effects, were genotyped by the 5' nuclease assay.
RESULTS: Multivariate Cox regression analysis adjusted for age and tumour stage showed increased risk for progression or death for carriers of the rare allele (G-allele) of single nucleotide polymorphism (SNP) rs1990172 (hazard ratios (HR) = 2.26; p = 0.004 and HR = 3.13; p = 0.001 for event-free survival and overall survival, respectively). In addition, we were able to demonstrate an adverse effect on cancer prognosis for carriers of the rare allele (T-allele) of SNP rs975263 (HR = 2.17; p = 0.007 and HR = 2.80; p = 0.003 for event-free survival and overall survival, respectively). The rare allele (C-allele) of SNP rs3735615 showed a significant protective impact on event-free survival as well as overall survival (HR = 0.25; p = 0.001, and HR = 0.16; p = 0.001, respectively).
CONCLUSIONS: This study provides first evidence that MACC1 polymorphisms are associated with clinical outcome for HER2-positive breast cancer patients. Further studies are warranted to validate these findings.

Fujinaga T, Kumamaru W, Sugiura T, et al.
Biological characterization and analysis of metastasis-related genes in cell lines derived from the primary lesion and lymph node metastasis of a squamous cell carcinoma arising in the mandibular gingiva.
Int J Oncol. 2014; 44(5):1614-24 [PubMed] Related Publications
Controlling metastatic lesions is an important part of improving cancer prognosis, in addition to controlling the primary lesion. There have been numerous histological studies on primary and metastatic lesions, but little basic research has been performed using cell lines from primary and metastatic lesions belonging to the same patient. In this study, we successfully established a cell line derived from lower gingival carcinoma (WK2) as well as a line derived from secondary cervical lymph node metastasis (WK3F) through primary cultures of tissue from a patient with oral squamous cell carcinoma. We then investigated the biological characteristics of the cancer cell lines from these primary and metastatic lesions and analyzed metastasis-related genes. Comparison of the biological characteristics in vitro showed that WK3F had higher cell proliferation ability and shorter cell doubling time than WK2. WK3F also had increased cell migratory ability and higher invasive and self-replication abilities. Heterotransplantation into nude mice resulted in high tumor formation rates in the tongue and high metastasis rates in the cervical lymph nodes. Changes in WK2 and WK3F gene expression were then comprehensively analyzed using microarrays. Genes with increased expression in WK3F compared to WK2 were extracted when the Z-score was ≥2.0 and the ratio was ≥5.0, while genes with reduced expression in WK3F compared to WK2 were extracted when the Z-score was ≤-2.0 and the ratio was ≤0.2; differences were found in 604 genes. From these, MAGEC1 (88.0-fold), MMP-7 (18.6-fold), SNAI1 (6.6-fold), MACC1 (6.2-fold), and HTRA1 (0.012-fold) were selected as metastasis-related candidate genes. The results suggest that these molecules could be important for clarifying the mechanisms that regulate metastasis and provide new therapeutic targets for inhibiting tumor invasion.

Chen XP, Ren XP, Lan JY, et al.
Analysis of HGF, MACC1, C-met and apoptosis-related genes in cervical carcinoma mice.
Mol Biol Rep. 2014; 41(3):1247-56 [PubMed] Related Publications
To understand the underlying pharmacological basis and the molecular mechanism of Taxol in therapy of cervical carcinoma (CC) disease, we need to explore the effect of Taxol on CC-related genes and pro-apoptosis and anti-apoptosis genes expression. Immunohistochemistry, western blot and reverse transcription-polymerase chain reaction were applied to examine postive expression levels of Bcl-2, Bax and Caspase-3, HGF, MACC1, Caspase-3 and C-met proteins and MACC1 mRNA expression in tumour of CC mice. Results showed that treatment of Taxol could increase the inhibition rate of tumour growth, positive expression levels of Caspase-3, Bax and decrease positive expression levels of Bcl-2 and Bcl-2/Bax, expression levels of HGF, MACC1 and C-met proteins and MACC1 mRNA in tumour tissue of CC mice. It can be concluded that inhibitory activity of Taxol against tumour growth in CC mice is closely associated with its modulating positive expression of Bcl-2, Bax, Caspase-3, expression of HGF, MACC1, Caspase-3 and C-met proteins and MACC1 mRNA in tumour of CC mice. In conclusion, HGF, MACC1 and C-met genes involve into malignant cervical tumors occurrence, development and prognosis, and might become potential molecular target therapy site of cervical cancer. Taxol intervention may serve as a multi-targeted CC therapeutic capable of inducing selective cancer cell death.

Zheng Z, Gao S, Yang Z, et al.
Single nucleotide polymorphisms in the metastasis-associated in colon cancer-1 gene predict the recurrence of hepatocellular carcinoma after transplantation.
Int J Med Sci. 2014; 11(2):142-50 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The newly identified metastasis-associated in colon cancer-1 (MACC1) gene is involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis in a variety of malignancies. Overexpression of MACC1 gene is a prognostic marker for poor outcome of hepatocellular carcinoma (HCC) patients. However, the association between genetic polymorphisms of MACC1 gene and poor outcome in HCC has been not been performed. We therefore investigated the correlation of MACC1 single nucleotide polymorphisms (SNPs) with tumor recurrence and overall survival in HCC patients undergoing liver transplantation (LT).
METHODS: The study included 187 HCC patients treated with LT. Five polymorphisms in the MACC1 gene (rs1990172, rs3735615, rs4721888, rs2241056, rs975263) were genotyped in 183 cases of tumorous tissue sample and 117 cases of adjacent normal tissue sample using SNaP-Shot assays. The association of SNPs with tumor recurrence and overall survival was then analyzed by additive, dominant, recessive, and overdominant models in a cohort of 156 HCC patients.
RESULTS: In terms of tumor recurrence, heterozygous of SNP rs1990172 and SNP rs975263 showed a significant high risk of relapse using univariate and multivariate analysis (overdominant, HR(95%CI)=2.27 [1.41-3.66], P=0.001; HR(95%CI)=2.16 [1.37-3.39], P=0.001). But the difference between heterozygous of these two SNPs and overall survival did not reach a significance in all models. The other three investigated SNPs were not significantly associated with tumor recurrence and overall survival (P>0.05). In addition, we found no significant difference in genotype frequencies between HCC and controls.
CONCLUSIONS: Our data suggest that SNP rs1990172 and SNP rs975263 in the MACC1 gene may be potential genetic markers for HCC recurrence in LT patients.

Kuo IY, Wu CC, Chang JM, et al.
Low SOX17 expression is a prognostic factor and drives transcriptional dysregulation and esophageal cancer progression.
Int J Cancer. 2014; 135(3):563-73 [PubMed] Related Publications
The transcriptional network of the SRY (sex determining region Y)-box 17 (SOX17) and the prognostic impact of SOX17 protein expression in human cancers remain largely unclear. In this study, we evaluated the prognostic effect of low SOX17 protein expression and its dysregulation of transcriptional network in esophageal squamous cell carcinoma (ESCC). Low SOX17 protein expression was found in 47.4% (73 of 154) of ESCC patients with predicted poor prognosis. Re-expression of SOX17 in ESCC cells caused reduced foci formation, cell motility, decreased ESCC xenograft growth and metastasis in animals. Knockdown of SOX17 increased foci formation in ESCC and normal esophageal cells. Notably, 489 significantly differential genes involved in cell growth and motility controls were identified by expression array upon SOX17 overexpression and 47 genes contained putative SRY element in their promoters. Using quantitative chromatin immunoprecipitation-PCR and promoter activity assays, we confirmed that MACC1, MALAT1, NBN, NFAT5, CSNK1A1, FN1 and SERBP1 genes were suppressed by SOX17 via the SRY binding-mediated transcriptional regulation. Overexpression of FN1 and MACC1 abolished SOX17-mediated migration and invasion suppression. The inverse correlation between SOX17 and FN1 protein expression in ESCC clinical samples further strengthened our conclusion that FN1 is a transcriptional repression target gene of SOX17. This study provides compelling clinical evidence that low SOX17 protein expression is a prognostic biomarker and novel cell and animal data of SOX17-mediated suppression of ESCC metastasis. We establish the first transcriptional network and identify new suppressive downstream genes of SOX17 which can be potential therapeutic targets for ESCC.

Chai H, Yang Y
Effects of MACC1 siRNA on biological behaviors of HeLa.
Arch Gynecol Obstet. 2014; 289(6):1271-80 [PubMed] Related Publications
PURPOSE: Metastasis-associated in colon cancer 1 (MACC1) has been shown to play a critical role in several types of cancer. The purposes of this study were to evaluate MACC1 expression in cervical cancer and determine role of MACC1 small interference RNA (siRNA) in the growth and progression of cervical cancer.
METHODS: Immunohistochemical analysis of MACC1 expression was performed in different cervical lesion tissues. siRNA knockdown of MACC1 was performed. Cytoskeletal staining, RT-PCR, Western blot technology, transwell migration, MTT, and flow cytometry were used for identification of the functional roles of MACC1 siRNA in HeLa cells.
RESULTS: Immunohistochemistry demonstrated that MACC1 overexpression was detected in cervical cancer tissues. MACC1 siRNA transfection remarkably affected HeLa cell biological behaviors. Expression of MACC1 in HeLa cells was significantly down-regulated by MACC1 siRNA. In addition, knockdown of MACC1 in HeLa cells caused a significant decrease in cell proliferation or migration, and increased cell apoptosis rate. Flow cytometry showed that MACC1 siRNA may inhibit cell proliferation by interfering with cell mitosis and cell cycle progression.
CONCLUSIONS: These results suggest that MACC1 is a novel biomarker for cervical cancer diagnosis and a target for therapeutic interventions. Decreasing MACC1 expression by siRNA may prove to be an effective genetic therapy strategy.

Wang Z, Li Z, Wu C, et al.
MACC1 overexpression predicts a poor prognosis for non-small cell lung cancer.
Med Oncol. 2014; 31(1):790 [PubMed] Related Publications
The expression of metastasis-associated in colon cancer-1 (MACC1) in non-small cell lung cancer (NSCLC) and its association with pathological characteristics and prognosis for NSCLC patients were investigated retrospectively. The expression of MACC1 was evaluated through immunohistochemical staining of tissue microarrays from 180 samples of resected lung cancer tissues and adjacent normal lung tissues. MACC1 protein and mRNA expression were also examined from lung cancer cell lines with different metastatic potentials, 28 pairs of samples of resected fresh non-small cell lung cancer tissues, and adjacent normal lung tissues. Immunohistochemical staining of tissue microarrays showed that MACC1 was located in the cytoplasm. In addition, the expression of MACC1 protein in NSCLC was significantly higher compared to adjacent normal tissues (P < 0.001). The expression of MACC1 was positively associated with differentiation grade (P = 0.020), postoperative pathological TNM stage (P = 0.033), and lymph node metastasis (P = 0.028). Disease-free survival (DFS) and overall survival (OS) for the high MACC1 expression group were lower than the low expression group; univariate and multivariate regression analyses showed that MACC1 was an independent prognostic indicator for DFS (HR 3.124, P = 0.01) and OS (HR 2.905, P = 0.01) in NSCLC patients. The expression of MACC1 protein and mRNA was also upregulated in highly metastatic human lung cancer. In conclusion, the overexpression of MACC1 protein and mRNA may represent a potentially useful biomarker for the prognosis of NSCLC patients and might be involved in progression of NSCLC.

Hagemann C, Fuchs S, Monoranu CM, et al.
Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.
Neuro Oncol. 2013; 15(12):1696-709 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis-associated in colon cancer 1 (MACC1) has been established as an independent prognostic indicator of metastasis formation and metastasis-free survival for patients with colon cancer and other solid tumors. However, no data are available concerning MACC1 expression in human astrocytic tumors. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor of adulthood, and due to its invasive and rapid growth, patients have unfavorable prognoses. Although these tumors rarely metastasize, their invasive and migratory behavior is similar to those of metastatic cells of tumors of different origin. Thus, we hypothesized that MACC1 may be involved in progression of human gliomas.
METHODS: We performed real-time measurements of proliferation and migration in MACC1-transfected GBM cell lines (U138, U251) and evaluated tumor formation in organotypic hippocampal slice cultures of mice. Semiquantitative and quantitative real-time reverse transcription PCR analyses were performed for MACC1 and for its transcriptional target c-Met in human astrocytoma of World Health Organization grade II (low-grade astrocytoma) and GBM biopsies. Data were validated by MACC1 immunohistochemistry in independent matched samples of low-grade astrocytoma and GBM.
RESULTS: MACC1 increases the proliferative, migratory, and tumor-formation abilities of GBM cells. The c-Met inhibitor crizotinib reduced MACC1-induced migration and tumor formation in organotypic hippocampal slice cultures of mice. Analyzing patients' biopsies, MACC1 expression increased concomitantly with increasing World Health Organization grade. Moreover, MACC1 expression levels allowed discrimination of dormant and recurrent low-grade astrocytomas and of primary and secondary GBM. Strong MACC1 expression correlated with reduced patient survival.
CONCLUSIONS: MACC1 may represent a promising biomarker for prognostication and a new target for treatment of human gliomas.

Ren B, Zakharov V, Yang Q, et al.
MACC1 is related to colorectal cancer initiation and early-stage invasive growth.
Am J Clin Pathol. 2013; 140(5):701-7 [PubMed] Related Publications
OBJECTIVES: To investigate metastasis associated in colon cancer 1 (MACC1) and MET expression in colorectal adenoma, Tis, early-stage invasive (T1 and T2), and advanced adenocarcinoma with liver metastasis using immunohistochemistry.
METHODS: Ninety-three paraffin-embedded colorectal tumor specimens were immunohistochemically analyzed for MACC1 and MET protein expression.
RESULTS: MACC1 expression was upregulated in the transition from adenoma to Tis; its expression was further elevated during tumor progression from Tis to early invasive carcinoma. MET expression was constant from adenoma to Tis and to T1 but significantly increased as tumor progression to T2. Both MACC1 and MET expression were enhanced in advanced carcinoma with liver metastasis.
CONCLUSIONS: Stepwise elevation of MACC1 expression in key points of colorectal cancer development suggests that MACC1 may contribute to cancer initiation and early invasive growth. High expression of both MACC1 and MET may relate to distant metastasis.

Zhang K, Zhang Y, Zhu H, et al.
High expression of MACC1 predicts poor prognosis in patients with osteosarcoma.
Tumour Biol. 2014; 35(2):1343-50 [PubMed] Related Publications
Increasing evidence has demonstrated that high metastasis-associated in colon cancer-1 (MACC1) level is tightly associated with the development, progression, and poor prognosis of a variety of tumors. However, the relationship between MACC1 and the occurrence, development, and progression of osteosarcoma (OS) remains to be clarified. To facilitate and deepen the understanding of the associations of MACC1 with the development and progression of OS, in the current study, we detected the expressions of MACC1 mRNA and protein, and investigated the relationship between MACC1 expression and prognosis of the patients with OS. Our findings demonstrated that expressions of MACC1 mRNA and protein in OS tissues were significantly higher than those in paired normal bone tissues (P < 0.05). Additionally, the level of MACC1 mRNA in the patients with higher clinical stage and distant metastasis was markedly higher than those with lower clinical stage and without metastasis (P < 0.05). Furthermore, high MACC1 level was closely correlated with clinical stage and distant metastasis (P < 0.05), but not related to the patients' age, gender, tumor size, and anatomical location (P > 0.05). Stepwise investigation revealed that survival time of the patients with high MACC1 level was obviously lower than that with low MACC1 level (P < 0.05). Collectively, our data suggest that MACC1 may play important roles in the development and progression of OS, and thus may be considered as a novel molecular target for therapy of the patients with OS.

Yang T, Kong B, Kuang YQ, et al.
Overexpression of MACC1 protein and its clinical implications in patients with glioma.
Tumour Biol. 2014; 35(1):815-9 [PubMed] Related Publications
Metastasis associated in colon cancer 1 (MACC1) has been regarded as a novel potential therapeutic target for multiple cancers. However, the impact of MACC1 in glioma remains unclear. The aim of this study was to analyze the correlation of MACC1 expression with the clinicopathological features of glioma. MACC1 mRNA and protein expression levels in human glioma tissues were detected by quantitative real-time polymerase chain reaction and immunohistochemistry assays, respectively. MACC1 mRNA and protein expression were both significantly higher in glioma tissues than in corresponding noncancerous brain tissues (both P < 0.001). In addition, statistical analysis suggested that high MACC1 expression was significantly correlated with advanced pathological grade (P = 0.004) and that patients with high expression of MACC1 protein exhibited a poorer prognosis than those with low MACC1 expression. Furthermore, Cox multivariate analysis showed that MACC1 overexpression was an independent prognostic factor for predicting the overall survival of glioma patients. In conclusion, expression of MACC1 in glioma could be adopted as a candidate biomarker for the diagnosis of clinical stage and for assessing prognosis, indicating for the first time that MACC1 may play an important role in the tumor development and progression in glioma. MACC1 might be considered as a novel therapeutic target against this cancer.

Stein U
MACC1 - a novel target for solid cancers.
Expert Opin Ther Targets. 2013; 17(9):1039-52 [PubMed] Related Publications
INTRODUCTION: The metastatic dissemination of primary tumors is directly linked to patient survival in many tumor entities. The previously undescribed gene metastasis-associated in colon cancer 1 (MACC1) was discovered by genome-wide analyses in colorectal cancer (CRC) tissues. MACC1 is a tumor stage-independent predictor for CRC metastasis linked to metastasis-free survival.
AREAS COVERED: In this review, the discovery of MACC1 is briefly presented. In the following, the overwhelming confirmation of these data is provided supporting MACC1 as a new remarkable biomarker for disease prognosis and prediction of therapy response for CRC and also for a variety of additional forms of solid cancers. Lastly, the potential clinical utility of MACC1 as a target for prevention or restriction of tumor progression and metastasis is envisioned.
EXPERT OPINION: MACC1 has been identified as a prognostic biomarker in a variety of solid cancers. MACC1 correlated with tumor formation and progression, development of metastases and patient survival representing a decisive driver for tumorigenesis and metastasis. MACC1 was also demonstrated to be of predictive value for therapy response. MACC1 is a promising therapeutic target for anti-tumor and anti-metastatic intervention strategies of solid cancers. Its clinical utility, however, must be demonstrated in clinical trials.

Juneja M, Ilm K, Schlag PM, Stein U
Promoter identification and transcriptional regulation of the metastasis gene MACC1 in colorectal cancer.
Mol Oncol. 2013; 7(5):929-43 [PubMed] Related Publications
MACC1, Metastasis associated in colon cancer 1, is a newly identified prognostic biomarker for colorectal cancer metastasis and patient survival, when determined in the primary tumor or patient blood. MACC1 induces cell motility and proliferation in cell culture and metastasis in mouse models. MACC1 acts as a transcriptional regulator of the receptor tyrosine kinase gene Met via binding to its promoter. However, no information about the promoter of the MACC1 gene and its transcriptional regulation has been reported so far. Here we report the identification of the MACC1 promoter using a promoter luciferase construct that directs transcription of MACC1. To gain insights into the essential domains within this promoter region, we constructed 5' truncated deletion constructs. Our results show that the region from -426 to -18 constitutes the core promoter and harbors functional motifs for the binding of AP-1, Sp1, and C/EBP transcription factors as validated by site directed mutagenesis study. Using electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we demonstrated the physical interaction of these transcription factors to a minimal essential MACC1 core promoter sequence. Knock down of these transcription factors using RNAi strategy reduced MACC1 expression (P < 0.001), and resulted in decrease of cell migration (P < 0.01) which could be specifically rescued by ectopic overexpression of MACC1. In human colorectal tumors, expression levels of c-Jun and Sp1 correlated significantly to MACC1 (P = 0.0007 and P = 0.02, respectively). Importantly, levels of c-Jun and Sp1 also showed significant correlation to development of metachronous metastases (P = 0.01 and P = 0.001, respectively). This is the first study identifying the MACC1 promoter and its transcriptional regulation by AP-1 and Sp1. Knowledge of the transcriptional regulation of the MACC1 gene will implicate in enhanced understanding of its role in cancer progression and metastasis.

Xie C, Wu J, Yun J, et al.
MACC1 as a prognostic biomarker for early-stage and AFP-normal hepatocellular carcinoma.
PLoS One. 2013; 8(5):e64235 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The metastasis-associated in colon cancer 1 gene (MACC1) has been found to be associated with cancer development and progression. The aim of this study was to investigate the prognostic value of MACC1 in early-stage and AFP-normal hepatocellular carcinoma (HCC).
METHODS: mRNA and protein levels of MACC1 expression in one normal liver epithelial cells THLE3 and 15 HCC cell lines were examined using reverse transcription-PCR and Western blot. MACC1 expression was also comparatively studied in 6 paired HCC lesions and the adjacent non-cancerous tissue samples. Immunohistochemistry was employed to analyze MACC1 expression in 308 clinicopathologically characterized HCC cases. Statistical analyses were applied to derive association between MACC1 expression scores and clinical staging as well as patient survival.
RESULTS: Levels of MACC1 mRNA and protein were higher in HCC cell lines and HCC lesions than in normal liver epithelial cells and the paired adjacent noncancerous tissues. Significant difference in MACC1 expression was found in patients of different TNM stages (P<0.001). Overall survival analysis showed that high MACC1 expression level correlated with lower survival rate (P = 0.001). Importantly, an inverse correlation between MACC1 level and patient survival remained significant in subjects with early-stage HCC or with normal serum AFP level.
CONCLUSIONS: MACC1 protein may represent a promising biomarker for predicting the prognosis of HCC, including in early-stage and AFP-normal patients.

Isella C, Mellano A, Galimi F, et al.
MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases.
Ann Surg. 2013; 257(6):1089-95 [PubMed] Related Publications
OBJECTIVE: Upon colon cancer metastasis resection in liver, disease outcome is heterogeneous, ranging from indolent to very aggressive, with early recurrence. The aim of this study is to investigate the capability of metastasis associated in colon cancer 1 (MACC1) levels measured in liver metastasis specimens to predict further recurrence of the disease.
METHODS: Gene expression and gene dosage of MACC1, hepatocyte growth factor (HGF), and hepatocyte growth factor receptor (MET) were assessed using quantitative realtime polymerase chain reaction on a cohort of 64 liver metastasis samples from patients with complete follow-up of 36 months and detailed clinical annotation. The most relevant mutations associated to prognosis in colorectal cancer, KRAS, and PIK3CA were assessed on the same specimens with Sanger sequencing.
RESULTS: Receiver operating characteristic (ROC) analysis revealed that MACC1 mRNA abundance is a good indicator of metastatic recurrence (AUC = 0.65, P < 0.05), whereas no such results were obtained with MET and HGF, nor with gene dosage. Generation of MACC1-based risk classes was capable of successfully separating patients into poor and good prognosis subgroups [hazard ratio (HR) = 5.236, 95% confidence interval (CI) = 1.2068-22.715, P < 0.05]. Also KRAS mutation was significantly associated with higher risk of recurrence (HR = 2.07, 95% CI = 1.048-4.09, P < 0.05). Cox regression multivariate analysis supported the independence of MACC1, but not KRAS, from known prognostic clinical information (Node Size HR = 3.155, 95% CI = 1.4418-6.905, P < 0.001, Preoperative carcinoembryonic antigen HR = 2.359, 95% CI = 1.0203-5.452, P < 0.05, MACC1 HR = 7.2739, 95% CI = 1.6584-31.905, P < 0.01).
CONCLUSIONS: MACC1, a new easily detectable biomarker in cancer, is an independent prognostic factor of recurrence after liver resection of colorectal cancer metastasis.

Wang L, Wu Y, Lin L, et al.
Metastasis-associated in colon cancer-1 upregulation predicts a poor prognosis of gastric cancer, and promotes tumor cell proliferation and invasion.
Int J Cancer. 2013; 133(6):1419-30 [PubMed] Related Publications
Metastasis-associated in colon cancer-1 (MACC1) is a newly identified oncogene, and little is known about its role in gastric cancer (GC). Our study was performed to investigate whether MACC1 influences the prognosis of GC patients and to explore the potential mechanisms involved. MACC1 expression was verified to be higher in GC tissues than in adjacent nontumorous tissues by Western blotting. A retrospective analysis of 361 GC patients (Stages I-IV) revealed that higher MACC1 expression was associated with more advanced disease, more frequent postoperative recurrence, more metastases and a higher mortality rate. The disease-free survival of Stage I-III patients and overall survival of Stage-IV patients were significantly worse when their tumors showed high MACC1 expression. To investigate the underlying mechanisms, MACC1 overexpression and downregulation were established in two GC cell lines (BGC-823 and MKN-28 cells). MACC1 overexpression significantly accelerated tumor growth and facilitated metastasis in athymic mice. MACC1 also promoted the proliferation, migration and invasion of both GC cell lines. Moreover, gastric MACC1 mRNA expression levels were significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT) in patients with GC. MACC1 overexpression upregulated mesenchymal-epithelial transition factor and induced changes to markers of EMT, whereas silencing of MACC1 reversed all these changes. These findings provide some novel insights into the role of MACC1, a gene that contributes to a poor prognosis of GC by promoting tumor cell proliferation and invasion as well as the EMT.

Gao J, Ding F, Liu Q, Yao Y
Knockdown of MACC1 expression suppressed hepatocellular carcinoma cell migration and invasion and inhibited expression of MMP2 and MMP9.
Mol Cell Biochem. 2013; 376(1-2):21-32 [PubMed] Related Publications
Expression of MACC1 (metastasis-associated in colon cancer-1) protein is associated with metastasis of various human cancers. This study analyzed MACC1 protein expression in hepatocellular carcinoma (HCC) tissue specimens and then investigated the effects of MACC1 knockdown on HCC cell migration and invasion, and gene expression levels. Sixty pairs of HCC and adjacent normal liver tissues from HCC patients were analyzed for MACC1 expression immunohistochemically. The HCC cell lines Hep3B, Huh7, MHCC97H, SMMC-7721, Bel-7402, and HepG2 and the normal liver cell line LO2 were used to assess expressions of MACC1 mRNA and MACC1 protein using qRT-PCR and western blot, respectively. MACC1 short hairpin RNA (shRNA) was used to knockdown MACC1 protein expression in Huh7 cells. Changes in the tumor phenotype of these cells were analyzed with wound healing assay and invasion assays, and differences in gene expression were evaluated via western blot. Immunofluorescence was used to locate MACC1 protein in the above cell lines. MACC1 was highly expressed in HCC tissues and the nuclear expression of MACC1 protein was associated with poor tumor differentiation and intrahepatic metastasis or portal invasion. Moreover, MACC1 mRNA and MACC1 protein was also expressed in HCC cell lines. Immunostaining showed that MACC1 protein was localized in both nuclei and cytoplasm of HCC cell lines and the nuclear localization of MACC1 protein was associated with increased aggressiveness of HCC in cell lines. Knockdown of MACC1 expression using MACC1-shRNA reduced Huh7 cell migration and invasion abilities, which was associated with downregulation of MMP2, MMP9, and c-Met proteins in Huh7 cells. Localization of MACC1 protein to the nucleus may predict HCC progression. Knockdown of MACC1 expression using MACC1 shRNA warrants further evaluation as a novel therapeutic strategy for control of HCC.

Tokarz P, Blasiak J
The role of microRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment.
Acta Biochim Pol. 2012; 59(4):467-74 [PubMed] Related Publications
microRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression by targeting specific mRNAs. microRNAs play a role in several physiological processes in the cell, including migration, proliferation, differentiation and apoptosis. Apart from their role in regular metabolism, abnormal profiles of miRNA expression accompany cancer transformation, including colorectal cancer (CRC) metastasis. microRNAs may play a role in each phase of CRC metastasis including angiogenesis, invasion, intravasation, circulation, extravasation and metastatic colonization. microRNA levels may serve as a predictive CRC marker, which was confirmed by the serum level of miR-29a targeting KLF4, a marker of cell stemness, and the plasma level of miR-221 down-regulating c-Kit, Stat5A and ETS1, which are signal transducers and transcription factor, respectively. In turn, the level of miR-143 in CRC cells decreasing the amount of MACC1 (metastasis-associated in colon cancer-1) and oncogenic KRAS protein, may be utilized as a prognostic marker. Also, single nucleotide polymorphisms of genes encoding miRNAs, including miR-423 and miR-608, which correlate with tumor recurrence, may be useful as diagnostic, prognostic and predictive indicators in CRC metastasis. Pre-miR-34a and pre-miR-199a decreased the level of Axl, a tyrosine-protein kinase receptor, so they can be considered as drugs in antimetastatic therapy. On the other hand, miR-222 targeting ADAM-17, a disintegrin and metalloproteinase, and miR-328 interacting with ABCG2, an ABC transporter, may overcome drug resistance of cancer cells. microRNAs may be considered in wide-range application to facilitate CRC metastasis diagnosis, prognosis, prediction and therapy, however, further clinical, epidemiological and in vitro studies should be conducted to verify their utility.

Stein U, Burock S, Herrmann P, et al.
Circulating MACC1 transcripts in colorectal cancer patient plasma predict metastasis and prognosis.
PLoS One. 2012; 7(11):e49249 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis is the most frequent cause of treatment failure and death in colorectal cancer. Early detection of tumors and metastases is crucial for improving treatment strategies and patient outcome. Development of reliable biomarkers and simple tests routinely applicable in the clinic for detection, prognostication, and therapy monitoring is of special interest. We recently identified the novel gene Metastasis-Associated in Colon Cancer 1 (MACC1), a key regulator of the HGF/Met-pathway. MACC1 is a strong prognostic biomarker for colon cancer metastasis and allows identification of high-risk subjects in early stages, when determined in patients' primary tumors. To overcome the limitation of a restricted number of molecular analyses in tumor tissue, the establishment of a non-invasive blood test for early identification of high-risk cancer patients, for monitoring disease course and therapy response is strongly needed.
METHODOLOGY/PRINCIPAL FINDINGS: For the first time, we describe a non-invasive assay for quantification of circulating MACC1 transcripts in blood of more than 300 colorectal cancer patients. MACC1 transcript levels are increased in all disease stages of the cancer patients compared to tumor-free volunteers. Highest MACC1 levels were determined in individuals with metastases (all P<0.05). Importantly, high MACC1 levels correlate with unfavorable survival (P<.0001). Combining MACC1 with circulating transcripts of the metastasis gene S100A4, a transcriptional target of the Wnt/β-catenin-pathway, improves survival prediction for newly diagnosed cancer patients.
CONCLUSION/SIGNIFICANCE: This blood-based assay for circulating MACC1 transcripts, which can be quantitated on a routine basis, is clinically applicable for diagnosis, prognosis, and therapeutic monitoring of cancer patients. Here we demonstrate the diagnostic and prognostic value of circulating MACC1 transcripts in patient plasma for metastasis and survival. Since MACC1 represents a promising target for anti-metastatic therapies, circulating MACC1 transcripts may prove to be an ideal read-out for monitoring therapeutic response of future interventions targeting MACC1-induced metastasis in cancer patients.

Nitsche U, Rosenberg R, Balmert A, et al.
Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer.
Ann Surg. 2012; 256(5):763-71; discussion 771 [PubMed] Related Publications
OBJECTIVES: Individualized risk assessment in patients with UICC stage II colon cancer based on a panel of molecular genetic alterations.
BACKGROUND: Risk assessment in patients with colon cancer and localized disease (UICC stage II) is not sufficiently reliable. Development of metachronous metastasis is assumed to be governed largely by individual tumor genetics.
METHODS: Fresh frozen tissue from 232 patients (T3-4, N0, M0) with complete tumor resection and a median follow-up of 97 months was analyzed for microsatellite stability, KRAS exon 2, and BRAF exon 15 mutations. Gene expression of the WNT-pathway surrogate marker osteopontin and the metastasis-associated genes SASH1 and MACC1 was determined for 179 patients. The results were correlated with metachronous distant metastasis risk (n = 22 patients).
RESULTS: Mutations of KRAS were detected in 30% patients, mutations of BRAF in 15% patients, and microsatellite instability in 26% patients. Risk of recurrence was associated with KRAS mutation (P = 0.033), microsatellite stable tumors (P = 0.015), decreased expression of SASH1 (P = 0.049), and increased expression of MACC1 (P < 0.001). MACC1 was the only independent parameter for recurrence prediction (hazard ratio: 6.2; 95% confidence interval: 2.4-16; P < 0.001). Integrative 2-step cluster analysis allocated patients into 4 groups, according to their tumor genetics. KRAS mutation, BRAF wild type, microsatellite stability, and high MACC1 expression defined the group with the highest risk of recurrence (16%, 7 of 43), whereas BRAF wild type, microsatellite instability, and low MACC1 expression defined the group with the lowest risk (4%, 1 of 26).
CONCLUSIONS: MACC1 expression predicts development of metastases, outperforming microsatellite stability status, as well as KRAS/BRAF mutation status.

Schmid F, Burock S, Klockmeier K, et al.
SNPs in the coding region of the metastasis-inducing gene MACC1 and clinical outcome in colorectal cancer.
Mol Cancer. 2012; 11:49 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer is one of the main cancers in the Western world. About 90% of the deaths arise from formation of distant metastasis. The expression of the newly identified gene metastasis associated in colon cancer 1 (MACC1) is a prognostic indicator for colon cancer metastasis. Here, we analyzed for the first time the impact of single nucleotide polymorphisms (SNPs) in the coding region of MACC1 for clinical outcome of colorectal cancer patients. Additionally, we screened met proto-oncogene (Met), the transcriptional target gene of MACC1, for mutations.
METHODS: We sequenced the coding exons of MACC1 in 154 colorectal tumors (stages I, II and III) and the crucial exons of Met in 60 colorectal tumors (stages I, II and III). We analyzed the association of MACC1 polymorphisms with clinical data, including metachronous metastasis, UICC stages, tumor invasion, lymph node metastasis and patients' survival (n = 154, stages I, II and III). Furthermore, we performed biological assays in order to evaluate the functional impact of MACC1 SNPs on the motility of colorectal cancer cells.
RESULTS: We genotyped three MACC1 SNPs in the coding region. Thirteen % of the tumors had the genotype cg (rs4721888, L31V), 48% a ct genotype (rs975263, S515L) and 84% a gc or cc genotype (rs3735615, R804T). We found no association of these SNPs with clinicopathological parameters or with patients' survival, when analyzing the entire patients' cohort. An increased risk for a shorter metastasis-free survival of patients with a ct genotype (rs975263) was observed in younger colon cancer patients with stage I or II (P = 0.041, n = 18). In cell culture, MACC1 SNPs did not affect MACC1-induced cell motility and proliferation.
CONCLUSION: In summary, the identification of coding MACC1 SNPs in primary colorectal tumors does not improve the prediction for metastasis formation or for patients' survival compared to MACC1 expression analysis alone. The ct genotype (rs975263) might be associated with a reduced survival for younger colon cancer patients in early stages. However, further studies with larger sample sizes are needed.

Zhang Y, Wang Z, Chen M, et al.
MicroRNA-143 targets MACC1 to inhibit cell invasion and migration in colorectal cancer.
Mol Cancer. 2012; 11:23 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis-related genes, providing potential therapeutic targets on anti-metastasis strategy. Metastasis-associated in colon cancer-1 (MACC1) has been newly identified to express highly in colorectal cancer (CRC) and promote tumor metastasis through transactivating metastasis-inducing HGF/MET signaling pathway. In this study, we investigated whether miRNA 143 is involved in the regulation of MACC1 and thus plays a functional role in CRC.
RESULTS: Using both in silico prediction and western blot assay, we found the previously reported tumor suppressive miR-143 targeted MACC1 in CRC. The direct interaction between them was confirmed by 3' UTR luciferase reporter gene. In concordance with the inhibitory effects induced by siRNA mediated knockdown of MACC1, restoration of miR-143 by mimics in SW620 cells significantly attenuated cell growth, migration and invasion. It is notable that combined treatment of miR-143 mimics and MACC1 siRNA induced synergistic inhibitory effects compared to either miR-143 mimics or MACC1 siRNA treatment alone. Conversely, reduction of miR-143 by inhibitors in SW480 cells apparently stimulated these phenotypes. Furthermore, we observed that miR-143 level was inversely correlated with MACC1 mRNA expression in CRC tissues.
CONCLUSIONS: Our findings newly described miR-143/MACC1 link and provided a potential mechanism for MACC1 dysregulation and contribution to CRC cell invasion. It may help to estimate the therapeutic utility of miR-143 in CRC.

Kawamura M, Saigusa S, Toiyama Y, et al.
Correlation of MACC1 and MET expression in rectal cancer after neoadjuvant chemoradiotherapy.
Anticancer Res. 2012; 32(4):1527-31 [PubMed] Related Publications
BACKGROUND: Metastasis associated in colon cancer 1 (MACC1) is a recently identified gene that plays a key role in regulating hepatocyte growth factor-MET signaling. In this study, we demonstrated the correlation and the clinical significance of MACC1 and MET expression in rectal cancer patients treated with chemoradiotherapy (CRT) followed by surgery.
MATERIALS AND METHODS: The expression of MACC1 and MET mRNA in residual cancer cells from 52 patients after CRT was determined by quantitative real-time polymerase chain reaction. Protein expression was also investigated by immunohistochemical staining.
RESULTS: MACC1 and MET expressions were positively correlated. Furthermore, these proteins were also co-expressed in immunohistochemical analyses. High expression of MACC1 or MET was associated with reduced relapse-free survival and the prognosis was worse when both genes were highly expressed.
CONCLUSION: Evaluation of MACC1 and MET expression may be useful for predicting prognosis in patients with rectal cancer treated with CRT followed by surgery.

Pichorner A, Sack U, Kobelt D, et al.
In vivo imaging of colorectal cancer growth and metastasis by targeting MACC1 with shRNA in xenografted mice.
Clin Exp Metastasis. 2012; 29(6):573-83 [PubMed] Related Publications
We previously identified the gene metastasis-associated in colon cancer-1 (MACC1) and demonstrated its important role for metastasis prediction in colorectal cancer. MACC1 induces cell motility and proliferation in vitro as well as metastasis in several mouse models. Here we report non-invasive real time imaging of inhibition of colorectal tumor progression and metastasis in xenografted mice by MACC1 shRNA. First, we demonstrated reduction of tumors and liver metastases by endpoint imaging of mice transplanted with MACC1 endogenously high expressing colorectal cancer cells and treated with shRNAs acting on MACC1 or Met. Next, we generated a novel bicistronic IRES vector simultaneously expressing the reporter gene firefly luciferase and MACC1 to ensure a direct correlation of bioluminescence signal with MACC1 expression. We transfected MACC1 endogenously low expressing colorectal cancer cells with this luciferase-IRES-MACC1 construct, transplanted them intrasplenically, and monitored MACC1 induced tumor growth and metastasis by in vivo imaging over time. Transfection of an IRES construct harboring the firefly luciferase reporter gene together with MACC1 lacking the SH3-domain reduced tumor growth and metastasis. Finally, we counteracted the luciferase-IRES-MACC1 induced effects by shRNA targeting MACC1 and monitored reduced tumor growth and metastasis by in vivo imaging over weeks. In summary, the new bicistronic luciferase-IRES-MACC1 construct is suitable for in vivo imaging of tumor progression and metastasis, and moreover, for imaging of therapy response such as treatment with MACC1 shRNA. Thereby, we provide proof-of-concept for employment of this MACC1-based in vivo model for evaluating therapeutic intervention strategies aiming at inhibition of tumor growth and metastasis.

Lang AH, Geller-Rhomberg S, Winder T, et al.
A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients.
BMC Cancer. 2012; 12:20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients.
METHODS: The study included 318 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032), capturing most of the common variants of the MACC1 locus, were genotyped by SNaPshot assays.
RESULTS: Over a mean follow up period of 5.3 (± 1.0) years, 94 deaths were recorded. Carriers of the G-allele of SNP rs1990172 showed a significantly decreased overall survival (additive HR = 1.38 [1.05-1.82]; p = 0.023). Multivariate analysis adjusted for age and UICC tumor stage confirmed this result (HR = 1.49 [1.12-1.98]; p = 0.007). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (p-values > 0.05).
CONCLUSIONS: For the first time, our study investigated the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings.

Migliore C, Martin V, Leoni VP, et al.
MiR-1 downregulation cooperates with MACC1 in promoting MET overexpression in human colon cancer.
Clin Cancer Res. 2012; 18(3):737-47 [PubMed] Related Publications
PURPOSE: MET, the tyrosine kinase receptor for hepatocyte growth factor, is frequently overexpressed in colon cancers with high metastatic tendency. We aimed to evaluate the role of its negative regulators, miR-1 and miR-199a*, and its transcriptional activator, the metastasis-associated in colon cancer 1 (MACC1), in controlling MET expression in human colon cancer samples.
EXPERIMENTAL DESIGN: The expression of MET, miR-1, miR-199a*, and MACC1 was evaluated by real-time PCR in 52 matched pairs of colorectal cancers and nontumoral surrounding tissues. The biological role of miR-1 in controlling MET expression and biological activity was assessed in colon cancer cells either by its forced expression or by AntagomiR-mediated inhibition.
RESULTS: MiR-1 was downregulated in 84.6% of the tumors and its decrease significantly correlated with MET overexpression, particularly in metastatic tumors. We found that concurrent MACC1 upregulation and miR-1 downregulation are required to elicit the highest increase of MET expression. Consistent with a suppressive role of miR-1, its forced in vitro expression in colon cancer cells reduced MET levels and impaired MET-induced invasive growth. Finally, we identified a feedback loop between miR-1 and MET, resulting in their mutual regulation.
CONCLUSIONS: This study identifies an oncosuppressive role of miR-1 in colorectal cancer in which it acts by controlling MET expression through a feedback loop. Concomitant downregulation of miR-1 and increase of MACC1 can thus contribute to MET overexpression and to the metastatic behavior of colon cancer cells.

Qiu J, Huang P, Liu Q, et al.
Identification of MACC1 as a novel prognostic marker in hepatocellular carcinoma.
J Transl Med. 2011; 9:166 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis-associated in colon cancer-1 (MACC1) is a newly identified gene that plays a role in colon cancer metastasis through upregulation of c-MET proto-oncogene (c-MET). However, the value of MACC1 as a potential biomarker for hepatocellular carcinoma (HCC) remains unknown.
METHODS: MACC1 mRNA expression in 128 HCC tissues was examined by quantitative polymerase chain reaction. To show the potential correlation of MACC1 and c-MET, c-MET was also analysed.
RESULTS: MACC1 was more highly expressed in HCC than in non-HCC tissues (P = 0.009). High MACC1 expression was significantly increased in cases with high alpha fetoprotein (AFP) (P = 0.025). A positive correlation was found between MACC1 and c-MET mRNAs (r = 0.235, P = 0.009). Both univariate and multivariate analyses revealed that MACC1 expression was associated with overall survival (OS) and disease-free survival (DFS). Moreover, stratified analysis showed that tumour-node-metastasis (TNM) stage I patients with high MACC1 levels had shorter OS and DFS than those with low MACC1.
CONCLUSIONS: MACC1 may identify low- and high-risk individuals with HCC and be a valuable indicator for stratifying the prognosis of TNM stage I patients. MACC1 may serve as a novel biomarker for HCC.

Zhang R, Shi H, Chen Z, et al.
Effects of metastasis-associated in colon cancer 1 inhibition by small hairpin RNA on ovarian carcinoma OVCAR-3 cells.
J Exp Clin Cancer Res. 2011; 30:83 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis-associated in colon cancer 1 (MACC1) is demonstrated to be up-regulated in several types of cancer, and can serve as biomarker for cancer invasion and metastasis. To investigate the relations between MACC1 and biological processes of ovarian cancer, MACC1 specific small hairpin RNA (shRNA) expression plasmids were used to investigate the effects of MACC1 inhibition on ovarian carcinoma OVCAR-3 cells.
METHODS: Expressions of MACC1 were detected in different ovarian tissues by immunohistochemistry. MACC1 specific shRNA expression plasmids were constructed and transfected into OVCAR-3 cells. Then, expressions of MACC1 were examined by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Cell proliferation was observed by MTT and monoplast colony formation assay. Flow cytometry and TUNEL assay were used to measure cell apoptosis. Cell migration was assessed by wound healing and transwell migration assay. Matrigel invasion and xenograft model assay were performed to analyze the potential of cell invasion. Activities of Met, MEK1/2, ERK1/2, Akt, cyclinD1, caspase3 and MMP2 protein were measured by Western blot.
RESULTS: Overexpressions of MACC1 were detected in ovarian cancer tissues. Expression of MACC1 in OVCAR-3 cells was significantly down-regulated by MACC1 specific small hairpin RNA. In OVCAR-3 cells, down-regulation of MACC1 resulted in significant inhibition of cell proliferation, migration and invasion, meanwhile obvious enhancement of apoptosis. As a consequence of MACC1 knockdown, expressions of Met, p-MEK1/2, p-ERK1/2, cyclinD1 and MMP2 protein decreased, level of cleaved capase3 was increased.
CONCLUSIONS: RNA interference (RNAi) against MACC1 could serve as a promising intervention strategy for gene therapy of ovarian carcinoma, and the antitumor effects of MACC1 knockdown might involve in the inhibition of HGF/Met and MEK/ERK pathways.

Wiśniewski JR, Ostasiewicz P, Mann M
High recovery FASP applied to the proteomic analysis of microdissected formalin fixed paraffin embedded cancer tissues retrieves known colon cancer markers.
J Proteome Res. 2011; 10(7):3040-9 [PubMed] Related Publications
Proteomic analysis of samples isolated by laser capture microdissection from clinical specimens requires sample preparation and fractionation methods suitable for small amounts of protein. Here we describe a streamlined filter-aided sample preparation (FASP) workflow that allows efficient analysis of lysates from low numbers of cells. Addition of carrier substances such as polyethylene glycol or dextran to the processed samples improves the peptide yields in the low to submicrogram range. In a single LC-MS/MS run, analyses of 500, 1000, and 3000 cells allowed identification of 905, 1536, and 2055 proteins, respectively. Incorporation of an additional SAX fractionation step at somewhat higher amounts enabled the analysis of formalin fixed and paraffin embedded human tissues prepared by LCM to a depth of 3600-4400 proteins per single experiment. We applied this workflow to compare archival neoplastic and matched normal colonic mucosa cancer specimens for three patients. Label-free quantification of more than 6000 proteins verified this technology through the differential expression of 30 known colon cancer markers. These included Carcino-Embryonic Antigen (CEA), the most widely used colon cancer marker, complement decay accelerating factor (DAF, CD55) and Metastasis-associated in colon cancer protein 1 (MACC1). Concordant with literature knowledge, mucin 1 was overexpressed and mucin 2 underexpressed in all three patients. These results show that FASP is suitable for the low level analysis of microdissected tissue and that it has the potential for exploration of clinical samples for biomarker and drug target discovery.

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