Gene Summary

Gene:KRT19; keratin 19, type I
Aliases: K19, CK19, K1CS
Summary:The protein encoded by this gene is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. Unlike its related family members, this smallest known acidic cytokeratin is not paired with a basic cytokeratin in epithelial cells. It is specifically expressed in the periderm, the transiently superficial layer that envelopes the developing epidermis. The type I cytokeratins are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:keratin, type I cytoskeletal 19
Source:NCBIAccessed: 18 August, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 18 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Oligonucleotide Array Sequence Analysis
  • Tumor Suppressor Gene
  • Tumor Antigens
  • Keratin-19
  • Uterine Cancer
  • Neoplasm Proteins
  • Uroplakin II
  • Signal Transduction
  • Cancer Gene Expression Regulation
  • Vesicular Transport Proteins
  • Up-Regulation
  • Transcriptome
  • Gene Expression Profiling
  • Chromosome 17
  • Promoter Regions
  • Sensitivity and Specificity
  • RT-PCR
  • Liver Cancer
  • Transfection
  • Vimentin
  • Hepatocellular Carcinoma
  • Base Sequence
  • Cell Proliferation
  • Staging
  • Uteroglobin
  • Epigenetics
  • Breast Cancer
  • Young Adult
  • Reproducibility of Results
  • Western Blotting
  • DNA Methylation
  • Circulating Cancer Cells
  • Epithelial-Mesenchymal Transition
  • Adenocarcinoma
  • Kidney Cancer
  • MicroRNAs
  • Messenger RNA
  • Tumor Markers
  • Receptors, Somatostatin
Tag cloud generated 18 August, 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: KRT19 (cancer-related)

Rodrigues MF, de Oliveira Rodini C, de Aquino Xavier FC, et al.
PROX1 gene is differentially expressed in oral cancer and reduces cellular proliferation.
Medicine (Baltimore). 2014; 93(28):e192 [PubMed] Related Publications
Homeobox genes are a family of transcription factors that play a pivotal role in embryogenesis. Prospero homeobox 1 (PROX1) has been shown to function as a tumor suppressor gene or oncogene in various types of cancer, including oral squamous cell carcinoma (OSCC). We have previously identified PROX1 as a downregulated gene in OSCC. The aim of this study is to clarify the underlying mechanism by which PROX1 regulates tumorigenicity of OSCC cells. PROX1 mRNA and protein expression levels were first investigated in 40 samples of OSCC and in nontumor margins. Methylation and amplification analysis was also performed to assess the epigenetic and genetic mechanisms involved in controlling PROX1 expression. OSCC cell line SCC9 was also transfected to stably express the PROX1 gene. Next, SCC9-PROX1-overexpressing cells and controls were subjected to proliferation, differentiation, apoptosis, migration, and invasion assays in vitro. OSCC samples showed reduced PROX1 expression levels compared with nontumor margins. PROX1 amplification was associated with better overall survival. PROX1 overexpression reduces cell proliferation and downregulates cyclin D1. PROX1-overexpressing cells also exhibited reduced CK18 and CK19 expression and transcriptionally altered the expression of WISP3, GATA3, NOTCH1, and E2F1. Our results suggest that PROX1 functions as a tumor suppressor gene in oral carcinogenesis.

Tang J, Zhuo H, Zhang X, et al.
A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma.
Cell Death Dis. 2014; 5:e1549 [PubMed] Related Publications
Location-associated long noncoding RNA (lncRNA) was reported to interact with target protein via a cis-regulatory process especially for the Flank10kb class lncRNA. Based on this theory, we aimed to explore the regulatory mechanisms of Linc00974 and KRT19 (an lncRNA beyond the Flank10kb class with protein) when we first confirmed the aberrant expression in hepatocellular carcinoma in a previous study. Knockdown of Linc00974 resulted in an inhibition of cell proliferation and invasion with an activation of apoptosis and cell cycle arrest in vitro, which was also validated by a subcutaneous and tail vein/intraperitoneal injection xenotransplantation model in vivo. We further investigated the interaction pattern of Linc00974 and KRT19. MiR-642 was identified, by acting as the competing endogenous RNA in regulating Linc00974 and KRT19. Linc00974 was increased owing to an abnormal hypomethylation promoter, which induced the upregulation of KRT19 via ceRNA interaction, resulting in the activation of the Notch and TGF-β pathways as detected by cDNA microarray. We also discovered Linc00974F-1 stably expressed in the plasma. By the combined analysis of Linc00974F-1 with CYFRA21-1, we found that these joint indicators predicted growth and metastasis of tumor in HCC patients. In conclusion, the combination of Linc00974 and KRT19 may be novel indices for clinical diagnosis of tumor growth and metastasis in HCC, while Linc00974 may become a potential therapeutic target for the prevention of HCC progression.

Masai K, Nakagawa K, Yoshida A, et al.
Cytokeratin 19 expression in primary thoracic tumors and lymph node metastases.
Lung Cancer. 2014; 86(3):318-23 [PubMed] Related Publications
BACKGROUND: The use of one-step nucleic acid amplification (OSNA), which allows for the rapid intraoperative detection of lymph node (LN) metastasis, is becoming more widely accepted in breast cancer. To provide basic data for the development of this method for lung tumors, we conducted a large-scale investigation of cytokeratin (CK) 19 expression in thoracic tumors.
PATIENTS AND METHODS: We examined CK19 expression in specimens from a total of 801 surgically resected samples of primary lung adenocarcinoma (ADC), squamous cell carcinoma (SQC), large-cell carcinoma (LCC), pleomorphic carcinoma (PC), large cell neuroendocrine carcinoma (LCNEC), small cell carcinoma (SCC), and carcinoid tumor (CT) as well as pleural malignant mesothelioma and lung metastatic deposits from breast cancer using tissue microarrays (TMAs) and whole sections. We also compared the CK19 expression status between primary sites and LN metastatic deposits.
RESULTS: The overall rate of CK19 expression as observed on TMAs and whole sections in the 801 analyzed cases was 88.0%. CK19 expression was detected in 94.6% of ADCs, 93.6% of SQCs, 54.5% of LCCs, 54.8% of PCs, 77.4% of LCNECs, 31.8% of SCCs, 34.0% of CTs, and 92.9% of malignant mesotheliomas. Expression of CK19 was also detected in 90.9% of lung metastatic deposits from breast carcinomas. CK19 expression was maintained between CK19-positive primary sites and the corresponding LN metastatic deposits. Of note, a portion of CK19-negative primary tumors showed upregulation of CK19 protein expression in LN metastases.
CONCLUSIONS: Most thoracic tumors, except for PCs, CTs, and SCCs, were positive for CK19. We also found that CK19 expression was maintained between CK19-positive primary tumors and the corresponding LN metastatic deposits. These results may be useful in the development of the OSNA method for the intraoperative detection of LN metastasis in non-small cell lung cancer (NSCLC).

Szasz AM, Szirtes I, Tihanyi B, et al.
Basaloid carcinoma of the pancreas--clinicopathological presentation and oncogenetic snapshot of a rare entity.
Virchows Arch. 2015; 466(2):237-41 [PubMed] Related Publications
We report a case of basaloid pancreatic carcinoma with clinical, pathological, and genomic data. The 73-year-old male patient had jaundice, acholic stool, diarrhea, weight loss, and a large, painless gall bladder. His GGT was highly elevated. The pancreatic head contained a tumor, which was resected by partial pancreatoduodenectomy with pancreato-gastric anastomosis, cholecystectomy, and lymphadenectomy. On gross examination, a 3.8-cm white firm nodule was found, which microscopically was composed of basaloid cell nests with a less than usual desmoplastic stromal background and focally PANIN. Immunohistochemical profile displayed strong CK5/6, CK19, p63, EGFR, vimentin, and evident CK14 expression and absence of expression of CK7, chromogranin, synaptophysin, and BRCA1. A high Ki-67 index and p53 expression were noted. Sequencing of the most frequent 46 oncogenes with ionTorrent (AmpliSeq PCR) method identified PIK3CA, KRAS, and TP53 genes as drivers and variants of the FGFR3, PDGFRA, KIT, KDR, EGFR, RET, and ATM genes. The tumor we report displays histopathological appearances similar to the previously described case and a genomic landscape fitting to the general population of pancreatic carcinomas. We hypothesize that this tumor may belong to the group of DNA damage repair-deficient pancreatic carcinoma subgroup.

Hao X, Liu Y, Li X, et al.
An intra-operative RT-LAMP method allows rapid and reliable detection of sentinel lymph node metastasis in breast cancer patients.
Virchows Arch. 2015; 466(2):169-76 [PubMed] Related Publications
The rapid determination of metastasis in sentinel lymph nodes (SLNs) of breast cancer patients plays a significant role in the selection of a surgery strategy. Although a previous one-step nucleic acid amplification assay that uses reverse-transcription (RT) loop-mediated isothermal amplification (LAMP) has showed specific advantages over traditional pathological examination, its target marker requires optimisation. In addition to epithelial-specific CK19, the internal control gene PBGD and the breast-specific PIP were included in the new method. After the RT-LAMP primers were designed and verified using a cell line, the performance of our method was evaluated by comparing it with the corresponding result of the Food and Drug Administration approved breast lymph node (BLN) assay and routine pathological examination. One hundred and seventy-four valid SLN samples from 101 patients were collected from five hospitals. The threshold of reaction time for CK19, PIP and PBGD was defined as 16, 20 and 20 min, respectively. Compared with the BLN assay, the concordance rate of our method was 95.4% (166/174). Statistical analysis revealed that the two methods are consistent (kappa = 0.890, P < 0.001). When compared with pathological examination, the performance of our method (sensitivity = 81.3%, specificity = 89.7%, kappa = 0.691, P < 0.001) was similar to that of the BLN assay (sensitivity = 87.5%, specificity = 84.9%, kappa = 0.668, P < 0.001). This result demonstrates the potential usefulness of our method in clinical practice. In conclusion, we preliminarily established an intra-operative diagnostic method that assimilates the merits of previous assays. In contrast with the BLN assay and pathological examination, our method can be completed in 30 min and shows high sensitivity, specificity and consistency, which we consider as promising for clinical application.

Wagner A, Mayr C, Bach D, et al.
MicroRNAs associated with the efficacy of photodynamic therapy in biliary tract cancer cell lines.
Int J Mol Sci. 2014; 15(11):20134-57 [PubMed] Free Access to Full Article Related Publications
Photodynamic therapy (PDT) is a palliative treatment option for unresectable hilar biliary tract cancer (BTC) showing a considerable benefit for survival and quality of life with few side effects. Currently, factors determining the cellular response of BTC cells towards PDT are unknown. Due to their multifaceted nature, microRNAs (miRs) are a promising analyte to investigate the cellular mechanisms following PDT. For two photosensitizers, Photofrin® and Foscan®, the phototoxicity was investigated in eight BTC cell lines. Each cell line (untreated) was profiled for expression of n=754 miRs using TaqMan® Array Human MicroRNA Cards. Statistical analysis and bioinformatic tools were used to identify miRs associated with PDT efficiency and their putative targets, respectively. Twenty miRs correlated significantly with either high or low PDT efficiency. PDT was particularly effective in cells with high levels of clustered miRs 25-93*-106b and (in case of miR-106b) a phenotype characterized by high expression of the mesenchymal marker vimentin and high proliferation (cyclinD1 and Ki67 expression). Insensitivity towards PDT was associated with high miR-200 family expression and (for miR-cluster 200a/b-429) expression of differentiation markers Ck19 and Ck8/18. Predicted and validated downstream targets indicate plausible involvement of miRs 20a*, 25, 93*, 130a, 141, 200a, 200c and 203 in response mechanisms to PDT, suggesting that targeting these miRs could improve susceptibility to PDT in insensitive cell lines. Taken together, the miRNome pattern may provide a novel tool for predicting the efficiency of PDT and-following appropriate functional verification-may subsequently allow for optimization of the PDT protocol.

Guo M, Li X, Zhang S, et al.
Real-time quantitative RT-PCR detection of circulating tumor cells from breast cancer patients.
Int J Oncol. 2015; 46(1):281-9 [PubMed] Related Publications
Circulating tumor cells (CTCs) were recognized as novel tumor biomarker for prognostic and predictive purposes in various cancers. Various detection technologies and devices have been developed to enumerate and characterize CTCs. Most of those approaches are based on the positive enrichment strategy and immunocytological techniques. However, the sensitivity of these approaches proved to be limited in metastatic tumors and the detection of early tumor cell dissemination was problematic. In the present study, we developed a novel CTC detection method by real-time RT-PCR technique in combination of negative enrichment strategy. The developed enrichment approach could recover more than 75% of spiked breast cancer cells from peripheral blood. The detection limit of duplex real-time RT-PCR assay using KRT19 and ERBB2 as targeted genes was consistently one breast tumor cell. Moreover, CTC detection by duplex real-time RT-PCR assay had higher detection sensitivity than that by immunostaining, especially in early breast cancer. In summary, the results of the present study indicated the potential clinical utilities of CTCs identification on breast cancer by duplex real-time RT-PCR in combination with negative enrichment.

Liszka L
Ductal adenocarcinoma of the pancreas usually retained SMAD4 and p53 protein status as well as expression of epithelial-to-mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis.
Pol J Pathol. 2014; 65(2):100-12 [PubMed] Related Publications
There are limited data on the biology of metastatic pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to compare the expression of immunohistochemical markers that may be involved in the development of metastatic disease in primary PDAC and in synchronous liver metastatic tissues. Thirty-two stains (corresponding to proteins encoded by 31 genes: SMAD4, TP53, ACTA2, CDH1, CDKN1A, CLDN1, CLDN4, CLDN7, CTNNB1, EGFR, ERBB2, FN1, KRT19, MAPK1/MAPK3, MAPK14, MKI67, MMP2, MMP9, MUC1 (3 antibodies), MUC5AC, MUC6, MTOR, MYC, NES, PTGS2, RPS6, RPS6KB1, TGFB1, TGFBR1, VIM) were evaluated using tissue microarray of 26 pairs of primary PDACs and their liver metastases. There were no significant differences in expression levels of examined proteins between primary and secondary lesions. In particular, metastatic PDAC retained the primary tumour's SMAD4 protein status in all and p53 protein status in all but one case. This surprising homogeneity also involved expression levels of markers of epithelial-to-mesenchymal transition as well as cell cycle regulators studied. In conclusion, the biological profiles of primary PDACs and their liver metastases seemed to be similar. Molecular alterations of PDAC related to a set of immunohistochemical markers examined in the present study were already present at the stage of localized disease.

Cierna Z, Mego M, Janega P, et al.
Matrix metalloproteinase 1 and circulating tumor cells in early breast cancer.
BMC Cancer. 2014; 14:472 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Matrix metalloproteinases (MMPs) are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play role in tumor dissemination and are an independent survival predictor in breast cancer (BC) patients. The aim of this study was to assess correlation between CTCs and tumor MMP1 in BC.
METHODS: Study included 149 primary BC patients treated by surgery from March 2012 to March 2013. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoietic cells using RossetteSep(TM) selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (TWIST1, SNAIL1, SLUG, ZEB1) and epithelial (CK19) gene transcripts by qRT-PCR. Patient samples with higher epithelial and/or mesenchymal gene transcripts than those of healthy donors (n = 60) were considered as CTC positive. Expression of MMP1 in surgical specimens was evaluated by immunohistochemistry.
RESULTS: CTCs were detected in 24.2% patients. CTCs exhibiting only epithelial markers were present in 8.7% patients, whereas CTCs with epithelial-mesenchymal transition (EMT) markers (CTC_EMT) were observed in 13.4% of patients and CTCs co-expressing both markers were detected in 2.0% patients. Patients with CTC_EMT in peripheral blood had significantly increased expression of MMP1 in tumor cells (p = 0.02) and tumor associated stroma (p = 0.05) than those of patients without CTC_EMT. In multivariate analysis, CTC_EMT and tumor grade were independently associated with MMP1 expression in cancer cells, while CTC_EMT and Ki67 were independently associated with MMP1 expression in cancer associated stroma.
CONCLUSION: Our data suggest link between MMP1 and CTCs with EMT phenotype and support role of MMPs and EMT in tumor dissemination.

Atik E, Guray M, Gunesacar R, et al.
Immunohistochemical analysis of thyroid follicular neoplasms and BRAF mutation correlation.
Indian J Cancer. 2014 Jan-Mar; 51(1):63-8 [PubMed] Related Publications
BACKGROUND: The accurate diagnosis of benign and malign thyroid tumors is very important for the clinical management of patients. The distinction of thyroid papillary carcinoma follicular variant and follicular adenoma can be difficult.
AIM: To investigate the alternative methods like immunohistochemistry and exon 15 in the BRAF gene 1799 T/A mutation analyses for distinguishing thyroid tumors.
MATERIALS AND METHODS: We applied immunohistochemical markers; CK19, HMWCK, Galectin-3, HBME-1 and Fibronectin and mutant allele-specific PCR amplification technique was used to determine 1799 T/A mutation within the BRAF gene. Formalin-fixed parafin embedded tissues from 45 surgically total resected thyroids, included 26 thyroid papillary carcinoma follicular variant (FV-TPC), 8 Follicular Adenoma (FA), 6 Minimal invasive follicular carcinoma (MIFC) and 5 Follicular Carcinoma (FC). Statistical Analyses Used: Pearson Chi-Square and Kruskal Wallis tests were performed.
RESULTS: There was a positive correlation between FV-TPC and HMWCK, CK 19, HBME1, Galectin 3, fibronectin (P < 0.05), but there was no correlation with FV-TPC and BRAF gene mutation (P > 0.05). HBME-1 and CK 19 stained strong and diffuse positive in FV-TPCs but weak and focal in FAs.
CONCLUSION: Our study suggests that morphologic features combined with immunohistochemical panel of HMWCK, CK19, HBME-1, Galectin-3 and fibronectin can help to distinguish benign and malign thyroid neoplasms and FV-TPC from follicular adenomas. BRAF gene 1799 T/A mutation has been non-specific but its detection can be a useful tool combined with immunohistochemistry for diagnosing FV-TPC.

Han TS, Hur K, Xu G, et al.
MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1.
Gut. 2015; 64(2):203-14 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
OBJECTIVE: Gastric cancer (GC) remains difficult to cure due to heterogeneity in a clinical challenge and the molecular mechanisms underlying this disease are complex and not completely understood. Accumulating evidence suggests that microRNAs (miRNAs) play an important role in GC, but the role of specific miRNAs involved in this disease remains elusive. We performed next generation sequencing (NGS)-based whole-transcriptome profiling to discover GC-specific miRNAs, followed by functional validation of results.
DESIGN: NGS-based miRNA profiles were generated in matched pairs of GCs and adjacent normal mucosa (NM). Quantitative RT-PCR validation of miR-29c expression was performed in 274 gastric tissues, which included two cohorts of matched GC and NM specimens. Functional validation of miR-29c and its gene targets was undertaken in cell lines, as well as K19-C2mE and K19-Wnt1/C2mE transgenic mice.
RESULTS: NGS analysis revealed four GC-specific miRNAs. Among these, miR-29c expression was significantly decreased in GC versus NM tissues (p<0.001). Ectopic expression of miR-29c mimics in GC cell lines resulted in reduced proliferation, adhesion, invasion and migration. High miR-29c expression suppressed xenograft tumour growth in nude mice. Direct interaction between miR-29c and its newly discovered target, ITGB1, was identified in cell lines and transgenic mice. MiR-29c expression demonstrated a stepwise decrease in wild type hyperplasia-dysplasia cascade in transgenic mice models of GC.
CONCLUSIONS: MiR-29c acts as a tumour suppressor in GC by directly targeting ITGB1. Loss of miR-29c expression is an early event in the initiation of gastric carcinogenesis and may serve as a diagnostic and therapeutic biomarker for patients with GC.

Hoon DS, Bernet L, Cano R, Viale G
Molecular analysis of sentinel lymph nodes and search for molecular signatures of the metastatic potential of breast cancer.
Q J Nucl Med Mol Imaging. 2014; 58(2):180-92 [PubMed] Related Publications
Molecular assays are a new and invaluable tool in the assessment of axillary lymph node status and metastatic potential of breast cancer. Many protocols for assessing the sentinel lymph node (SLN) status have been developed based on cytology and/or histology, showing that the rate of detection of metastasis increases with the number of histologic sections examined and with use of immunohistochemical staining in addition to conventional Hematoxylin & Eosin staining. However, full standardization of protocols for this procedure has not been achieved. Further attempts to increase sensitivity and specificity of sentinel node analysis include molecular biology-based techniques such as the real-time polymerase chain reaction (RT-PCR) and, more recently, one step nucleic acid amplification (OSNA). The latter technique, that has sensitivity close to 100% and extremely high specificity along with good reproducibility, allows analysis of the SLN in full with an intraoperative procedure in approximately 30 minutes. This highly standardized method permits to compare results between groups and predicts the probability of involvement of the remaining axillary lymph nodes based on the total tumor load of the SLN(s). Results of multicenter clinical trials suggest that OSNA allows a better personalization of patients' care based on the results of SLN analysis, because it offers criteria to select patient with metastatic SLN who will not receive additional benefit from axillary clearance. Due to the current controversy on the best treatment of the axilla after a positive SLN, the SLN copy number of CK19 mRNA can have a high impact on therapeutic decisions in this group of patients. Breast cancer is a highly heterogeneous group of diseases, characterized by remarkable differences in the histopathological features, response to treatment and clinical outcome. Most of the clinical and translational research efforts during the last decades aimed at identifying markers that would allow to predict the metastatic potential of early breast cancer, and hence to assess accurately its prognosis and to inform the choice of adjuvant systemic treatments. It is now clear that neoplastic transformation, tumor progression and response to treatment are driven and accompanied by the deregulated expression of hundred or thousand genes, whose status cannot be assessed by the currently established histopathological and immunohistochemical approach. The new molecular assays have elicited a great deal of expectations, and for the most part they have been enthusiastically welcomed as potentially offering new chances for a better and more personalized care of the patients. Many, however, are still reluctant to consider these assays ready for use in the clinical practice, and keep waiting for a confirmatory evidence of their utility when the results of ongoing clinical trials will be mature.

Cheng M, Chen Y, Zou D, et al.
The clinical utility of circulating tumor cells in breast cancer patients: detection by a quantitative assay of h-MAM gene expression.
Int J Biol Markers. 2014 Jul-Sep; 29(3):e268-78 [PubMed] Related Publications
The aim of this study was to evaluate tumor markers of molecular abnormalities that display tissue specificity, as to detect circulating tumor cells (CTCs) in breast cancer patients. Quantitative real-time RT-PCR was used to determine h-MAM, BCSG1, CK19, and c-erbB2 mRNA levels in peripheral blood (PB) of breast cancer patients. Results were compared with other epithelial cancers (lung or esophagus cancer), benign breast disease, and healthy individuals. We found that h-MAM mRNA was only detectable in the PB of patients with breast cancer (49 of 65, 75.4%), but not in patients with other epithelial cancers, benign breast disease, or healthy individuals. No significant differences in the expression level and positive detection rate of BCSG1, CK19, and c-erbB2 mRNA were observed between breast cancer and other epithelial cancers. Furthermore, the expression level and positive detection rate of h-MAM mRNA in PB were significantly correlated to the breast cancer pathologic stage (p=0.012 and p=0.015, respectively). Chemotherapy, radiotherapy, or total tumor resection (after 7 days of treatment) resulted in a significant decrease in the expression level of h-MAM mRNA in PB compared to the levels prior to the treatment (p<0.001). Importantly, an increase in h-MAM mRNA expression was detected in patients immediately after surgery, as well as 3 days post-surgery. These results indicate that the quantitative analysis of h-MAM mRNA is a useful tool for detecting CTCs in breast cancer patients, and can have a potential diagnostic utility in early micrometastasis, clinical evaluation of cancer treatment efficacy, and post-treatment monitoring of breast cancer patients.

Xiao S, Zhou Y, Jiang J, et al.
CD44 affects the expression level of FOS‑like antigen 1 in cervical cancer tissues.
Mol Med Rep. 2014; 9(5):1667-74 [PubMed] Related Publications
Cervical carcinoma is the second most prevalent type of malignancy in females worldwide. The crucial etiological factors involved in the development of cervical carcinoma include infection with the papillomavirus, and the structural or functional mutation of oncogenes and tumor suppressor genes. CD44 refers to a multifunctional family of type I transmembrane proteins. These proteins have been implicated in numerous biological processes, including cell adhesion, cell migration and metastasis. The present study examined the differences in the expression levels of ATP-binding cassette sub-family G member 2, CD24, CD44, CD133, cytokeratin (CK) 14 and CK19 between cervical cancer tissues and corresponding normal non-tumor tissues by flow cytometry. Then, the CD44+ or CD44‑ cells from cervical cancer tissues were sorted for identification and confirmation of differential expression by flow cytometry. The results demonstrated that the expression level of CD44 in cervical cancer tissues was higher than in the corresponding non-tumor normal tissues (t=3.12; P=0.0102). Compared with the CD44‑ cells, the FOS-like antigen 1 (Fra-1), nestin, nuclear receptor subfamily 4, group A, member 2, OCT4 and p63 genes were highly expressed in CD44+ cells. The fold changes were 3.55, 3.55, 2.46, 2.87 and 2.56, respectively (P<0.05). However, BMI1 polycomb ring finger oncogene, ck5, tumor protein p53 and lactotransferrin genes exhibited low expression levels in CD44+ cells. It was verified by western blot analysis and flow cytometry that Fra-1 was highly expressed in CD44+ cells. Fra-1 was a potential target of miR-19a and miR-19b. The expression of miR-19a and miR-19b was downregulated by ~50% in CD44+ cells compared with CD44‑ cells. These findings suggested that CD44 dysregulated the activation of the Fra‑1 gene. The interaction of Fra-1 and CD44 may therefore be important in cervical carcinoma.

Pappa KI, Rodolakis A, Christodoulou I, et al.
Comparative assessment of lymph node micrometastasis in cervical, endometrial and vulvar cancer: insights on the real time qRT-PCR approach versus immunohistochemistry, employing dual molecular markers.
Biomed Res Int. 2014; 2014:187684 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
To address the value of qRT-PCR and IHC in accurately detecting lymph node micrometastasis in gynecological cancer, we performed a systematic approach, using a set of dual molecular tumor-specific markers such as cytokeratin 19 (CK19) and carbonic anhydrase 9 (CA9), in a series of 46 patients (19 with cervical cancer, 18 with endometrial cancer, and 9 with vulvar cancer). A total of 1281 lymph nodes were analyzed and 28 were found positive by histopathology. Following this documentation, 82 lymph nodes, 11 positive and 71 negative, were randomly selected and further analyzed both by IHC and qRT-PCR for CK19 and CA9 expression. All 11 (100%) expressed CK19 by IHC, while only 6 (54.5%) expressed CA9. On the contrary, all the histologically negative for micrometastases lymph nodes were also negative by IHC analysis for both markers. The comparative diagnostic efficacy of the two markers using qRT-PCR, however, disclosed that the analysis of the same aliquots of the 82 lymph nodes led to 100% specificity for the CK19 biomarker, while, in contrast, CA9 failed to recapitulate a similar pattern. These data suggest that qRT-PCR exhibits a better diagnostic accuracy compared to IHC, while CK19 displays a consistent pattern of detection compared to CA9.

Chan AW, Tong JH, Chan SL, et al.
Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma.
Histopathology. 2014; 64(7):935-50 [PubMed] Related Publications
AIMS: The expression of stemness markers in hepatocellular carcinoma (HCC) is suggested to be associated with poor clinical outcome after surgical resection. There are few data on their independent prognostic role in addition to the existing AJCC TNM staging system.
METHODS AND RESULTS: The immunohistochemical expression of CD133, EpCAM, CK19 and CD56 was studied in a cohort of 282 surgical specimens collected from patients undergoing resection of primary HCC. CD133-positive HCCs were usually smaller in size (P = 0.002) and arose more frequently in cirrhotic liver (P = 0.002). CD133 expression was an independent prognostic factor for overall survival (hazard ratio 2.30, P < 0.001), and a highly potent prognostic factor in patients with stage I disease (hazard ratio 3.91, P = 0.001). EpCAM expression was associated with younger age (P < 0.001), smaller tumour size (P = 0.018) and poorer histological differentiation (P = 0.042). EpCAM immunoreactivity was an independent factor for disease-free survival in HCCs at all stages (hazard ratio 2.05, P = 0.001), stage II (hazard ratio 3.66, P = 0.010) and stages III/IV (hazard ratio 3.22, P = 0.001). Neither CK19 nor CD56 offered any independent prognostic value.
CONCLUSION: The prognostic role of CD133 was most significant in TNM stage I disease, while the prognostic role of EpCAM was more apparent in more advanced TNM stages.

Xu M, Xie F, Qian G, et al.
Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma.
BMC Cancer. 2014; 14:65 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: The role of ductular reaction (DR) in hepatocellular carcinoma (HCC) remains to be elucidated.
METHODS: In this study, we tried to uncover possible effect by correlating peritumoral DR in a necroinflammatory microenvironment with postoperative prognosis in HCC. The expression of peritumoral DR/CK19 by immunohistochemistry, necroinflammation and fibrosis were assessed from 106 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated.
RESULTS: Peritumoral DR significantly correlated with necroinflammation (r = 0.563, p = 3.4E-10), fibrosis (r = 0.435, p = 3.1E-06), AFP level (p = 0.010), HBsAg (p = 4.9E-4), BCLC stage (p = 0.003), TNM stage (p = 0.002), multiple nodules (p = 0.004), absence of tumor capsule (p = 0.027), severe microscopic vascular invasion (p = 0.031) and early recurrence (p = 0.010). Increased DR was significantly associated with decreased RFS/OS (p = 4.8E-04 and p = 2.6E-05, respectively) in univariate analysis and were identified as an independent prognostic factor (HR = 2.380, 95% CI = 1.250-4.534, p = 0.008 for RFS; HR = 4.294, 95% CI = 2.255-8.177, p = 9.3E-6 for OS) in multivariate analysis.
CONCLUSIONS: These results suggested that peritumoral DR in a necroinflammatory microenvironment was a poor prognostic factor for HCC after resection.

Ming M, Qiang L, Zhao B, He YY
Mammalian SIRT2 inhibits keratin 19 expression and is a tumor suppressor in skin.
Exp Dermatol. 2014; 23(3):207-9 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
SIRT2 is a member of the mammalian sirtuin family (SIRT1-7). As compared with other sirtuins, SIRT2 is found primarily in the cytoplasm. It regulates multiple physiological processes. However, the precise role of SIRT2 in skin cancer remains unclear. Here, we show that SIRT2 is downregulated in human skin cancer as compared with normal skin. SIRT2 deletion increases tumor growth in mice. SIRT2 knockdown upregulates the stem cell marker Keratin 19 (K19) in keratinocytes. In mice, SIRT2 deletion up-regulates K19 and K15 while it down-regulates the differentiation marker Loricrin in both normal skin and tumors. In skin tumors but not normal skin, SIRT2 deletion up-regulates the stem cell marker CD34 and increases the number of Ki67-positive cells. These findings indicate that SIRT2 is a tumor suppressor in the skin. Our findings add new insights into the role of SIRT2 in the molecular pathogenesis of skin cancer.

Gärtner S, Gunesch A, Knyazeva T, et al.
PTK 7 is a transforming gene and prognostic marker for breast cancer and nodal metastasis involvement.
PLoS One. 2014; 9(1):e84472 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Protein Tyrosin Kinase 7 (PTK7) is upregulated in several human cancers; however, its clinical implication in breast cancer (BC) and lymph node (LN) is still unclear. In order to investigate the function of PTK7 in mediating BC cell motility and invasivity, PTK7 expression in BC cell lines was determined. PTK7 signaling in highly invasive breast cancer cells was inhibited by a dominant-negative PTK7 mutant, an antibody against the extracellular domain of PTK7, and siRNA knockdown of PTK7. This resulted in decreased motility and invasivity of BC cells. We further examined PTK7 expression in BC and LN tissue of 128 BC patients by RT-PCR and its correlation with BC related genes like HER2, HER3, PAI1, MMP1, K19, and CD44. Expression profiling in BC cell lines and primary tumors showed association of PTK7 with ER/PR/HER2-negative (TNBC-triple negative BC) cancer. Oncomine data analysis confirmed this observation and classified PTK7 in a cluster with genes associated with agressive behavior of primary BC. Furthermore PTK7 expression was significantly different with respect to tumor size (ANOVA, p = 0.033) in BC and nodal involvement (ANOVA, p = 0.007) in LN. PTK7 expression in metastatic LN was related to shorter DFS (Cox Regression, p = 0.041). Our observations confirmed the transforming potential of PTK7, as well as its involvement in motility and invasivity of BC cells. PTK7 is highly expressed in TNBC cell lines. It represents a novel prognostic marker for BC patients and has potential therapeutic significance.

Xu R, Guo LJ, Xin J, et al.
Luciferase assay to screen tumour-specific promoters in lung cancer.
Asian Pac J Cancer Prev. 2014; 14(11):6557-62 [PubMed] Related Publications
OBJECTIVE: Specific promoters could improve efficiency and ensure the safety of gene therapy. The aim of our study was to screen examples for lung cancer.
METHODS: The firefly luciferase gene was used as a reporter, and promoters based on serum markers of lung cancer were cloned. The activity and specificity of seven promoters, comprising CEACAM5 (carcinoembryonic antigen, CEA), GRP (Gastrin-Releasing Peptide), KRT19 (cytokeratin 19, KRT), SFTPB (surfactant protein B, SP-B), SERPINB3 (Squamous Cell Carcinoma Antigen, SCCA), SELP (Selectin P, Granule Membrane Protein 140 kDa, Antigen CD62, GMP) and DKK1 (Dickkopf-1) promoters were compared in lung cancer cells to obtain cancer-specific examples with strong activity.
RESULTS: The CEACAM5, DKK1, GRP, SELP, KRT19, SERPINB3 and SFTPB promoters were cloned. Furthermore, we successfully constructed recombinant vector pGL-CEACAM5 (DKK1, GRP, SELP, KRT19, SERPINB3 and SFTPB) contained the target gene. After cells were transfected with recombinant plasmids, we found that the order of promoter activity from high to low was SERPINB3, DKK1, SFTPB, KRT19, CEACAM5, SELP and GRP and the order for promoters regarding specificity and high potential were SERPINB3, DKK1, SELP, SFTPB, CEACAM5, KRT19 and GRP.
CONCLUSION: The approach adopted is feasible to screen for new tumour specific promoters with biomarkers. In addition, the screened lung-specific promoters might have potential for use in lung cancer targeted gene therapy research.

Yoneda A, Taniguchi K, Torashima Y, et al.
The detection of gastric cancer cells in intraoperative peritoneal lavage using the reverse transcription--loop-mediated isothermal amplification method.
J Surg Res. 2014; 187(1):e1-6 [PubMed] Related Publications
INTRODUCTION: To detect a small number of malignant cells, we used a highly sensitive detection system that measures the expression levels of cytokeratin (CK) 19 messenger RNA by reverse transcription-loop-mediated isothermal amplification (RT-LAMP).
MATERIALS AND METHODS: We evaluated the clinical relevance of our novel diagnostic method with an RT-LAMP assay using CK19 as a target gene for the detection of free cancer cells in peritoneal lavage and assessed the clinical significance of the molecular diagnosis by survival analysis and frequency of recurrence, with a median follow-up period of 39 mo. We observed 52 patients with gastric cancer who underwent gastrectomy, bypass operation, and exploratory laparotomy.
RESULTS: Those 52 patients, who were subjected to both RT-LAMP and cytologic examination, were divided into the following three groups: (1) patients positive by cytology and RT-LAMP (CY+/LAMP+) (n = 9), (2) patients positive by LAMP and negative by cytology (CY-/LAMP+) (n = 12), and (3) patients negative by both cytology and LAMP (CY-/LAMP-) (n = 31). All patients with simultaneous peritoneal dissemination and positive cytology were positive on RT-LAMP. The results of RT-LAMP were statistically significant for recurrence by univariate analysis (P < 0.005). Cytology-positive cases had a very poor prognosis, and RT-LAMP-positive cases had a worse prognosis than RT-LAMP-negative cases.
CONCLUSIONS: Our findings suggest that CK19 RT-LAMP would be useful as an intraoperative diagnostic modality to detect patients with a high risk of recurrence even after clinically curative surgery, who thus require proper adjuvant therapy.

Mikulová V, Cabiňaková M, Janatková I, et al.
Detection of circulating tumor cells during follow-up of patients with early breast cancer: Clinical utility for monitoring of therapy efficacy.
Scand J Clin Lab Invest. 2014; 74(2):132-42 [PubMed] Related Publications
INTRODUCTION: Circulating tumor cells (CTCs) detection prior to and during therapy is considered as an independent and strong prognostic marker. The present study was designed to isolate and characterize CTCs in peripheral blood of an early breast cancer (BC) patient as a biomarker for monitoring treatments efficacy.
MATERIALS AND METHODS: In total, 54 early breast cancer patients undergoing neoadjuvant and/or adjuvant chemotherapy regimens were enrolled into a prospective study. CTC detection in blood was performed by AdnaTest BreastCancer(™) (AdnaGen AG, Germany), which is based on the detection of EpCAM, HER2 and MUC1 specific transcripts in enriched CTC-lysates. Additionally, cDNA from isolated CTCs and PBMC was used for qPCR gene expression analysis of TOP1, TOP2A, CTSD, ST6, CK19 and reference gene actin.
RESULTS: We found that CTCs can be detected in the peripheral blood of approximately 31% of early stage breast cancer patients. The presence of CTCs was detected in 36% ER positive, 32% PR positive and 30% HER2 positive patients. We found no correlation between CTCs and tumor size, tumor grade, histological grade and receptor status. Only 7% of all patients remained CTCs positive after adjuvant therapy. Gene expression analysis revealed a particular heterogeneity of the studied genes.
CONCLUSIONS: In conclusion, CTC detection may be a promising early marker of disease progression potentially enhancing the difficult therapeutic decisions. Further studies should, however, clearly demonstrate its utility for both the prediction of outcome and monitoring the effect of treatment.

Tamaki K, Tamaki N, Kamada Y, et al.
Non-invasive evaluation of axillary lymph node status in breast cancer patients using shear wave elastography.
Tohoku J Exp Med. 2013; 231(3):211-6 [PubMed] Related Publications
Less invasive procedures are currently required to examine the axillary lymph node status. Shear wave elastography with acoustic radiation force impulse provides objective and reproducible quantification of the intrinsic property of the soft tissue. In this study, we measured shear wave velocity of the axillary lymph nodes of patients with breast cancer using Virtual Touch Tissue Quantification (VTTQ). The degree of lymph node metastasis was evaluated by measuring the expression level of cytokeratin 19 (CK19) mRNA, a specific marker for breast cancer cells. The one-step nucleic acid amplification (OSNA) was used to determine the copy number of CK19 mRNA in 149 lymph node specimens of 149 primary breast cancer patients. Axillary lymph node status according to OSNA (copy number/μl) were categorized as 0-249 copies (-), 250-5,000 copies (+), and copy number > 5,000 (++). A category (-) represents no metastasis in the axillary lymph node. There were 121 patients with OSNA-, 9 with OSNA+ and 19 with OSNA++. The average velocities according to OSNA categories were 1.64 ± 0.42 m/second for OSNA-, 2.25 ± 0.78 m/second for OSNA+, and 2.79 ± 0.98 m/second for OSNA++. There were significant differences in the shear wave velocity between OSNA- and OSNA+ (P = 0.040) or OSNA++ (P < 0.001). The most optimal cutoff velocity to distinguish benign from metastasis is 1.44 m/second, as determined using the receiver operating characteristic method. The shear wave velocity measured with VTTQ could provide clinically useful information about axillary lymph node metastasis in patients with primary breast cancer.

Shi JH, Scholz H, Huitfeldt HS, Line PD
The effect of hepatic progenitor cells on experimental hepatocellular carcinoma in the regenerating liver.
Scand J Gastroenterol. 2014; 49(1):99-108 [PubMed] Related Publications
OBJECTIVE: Liver regeneration following hepatectomy can stimulate the growth of hepatocellular carcinoma (HCC), and major hepatectomy can be associated with activation of hepatic progenitor cells (HPCs). The aim of this study was to evaluate how HPCs influence the malignant potential of tumor cells in vitro and HCC tumor growth after surgery in a rodent model.
MATERIAL AND METHODS: Hepatoma cells (JM1) were cultured with conditioned medium (CM) from syngeneic HPCs (WB-F344). Growth rate, resistance to Adriamycin, and expression patterns for invasiveness and stemness were compared with naïve JM1. Microscopic HCC tumors from naïve JM1 or JM1 cultured with CM were inoculated in Fischer 344 rats undergoing 70% hepatectomy with or without simultaneous infusion of WB-F344. Tumor growth and invasiveness-related factors were compared. Buffalo rats were induced with Morris hepatoma cells. Liver tissue from both in vivo models was examined with regard to activation of cells with progenitor-like phenotype.
RESULTS: Co-culture with CM resulted in an increased resistance to Adriamycin and enhanced expressions of α-FP, MMP9, ABCG2, CD133, and SOX2, as well as the activation of ERK, AKT, WNT, and TGF-β1 pathways. Tumor size and metastases were significantly higher in groups with co-cultured cells or HPCs infusion. After 70% hepatectomy and tumor implantation, cells positive for α-FP, CK19, and CD133 were found, thus suggesting a progenitor-like phenotype in the setting of epithelial-mesenchymal transition.
CONCLUSION: HPCs have a marked effect on HCC cells in vitro and appear to stimulate the growth and malignant potential of experimental HCC tumors.

Noguchi A, Kikuchi K, Ohtsu T, et al.
Pulmonary tumors associated with the JC virus T-antigen in a transgenic mouse model.
Oncol Rep. 2013; 30(6):2603-8 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Many attempts to demonstrate the oncogenic role of the JC virus (JCV) have been partially successful in producing brain tumors, either by direct inoculation of JCV into the brain or in transgenic models in rodents. We previously reported the presence of JCV DNA with a relatively high incidence in pulmonary and digestive organs. However, we could not prove the oncogenic role of JCV. We prepared a transgene composed of the K19 promoter, specific to bronchial epithelium with the JCV T-antigen and established transgenic (TG) mice. Pulmonary tumors were detected without any metastasis in 2 out of 15 (13.3%) 16-month-old K19/JCV T-antigen TG mice. Using immunohistochemistry (IHC), these tumors showed JCV T-antigen, p53 and CK 19 expression, but not expression of nuclear and cytoplasmic β-catenin and insulin receptor substrate 1 (IRS1). IHC revealed the same expression pattern as in the bronchial epithelium of the TG mice. One tumor, which was examined with laser capture microdissection and molecular biological tools, demonstrated an EGFR mutation but not a K-ras mutation. We propose that the pulmonary tumors were derived from the JCV T-antigen in a TG mouse model. These findings shed light on pulmonary carcinogenesis.

Paniz Mondolfi AE, Jour G, Johnson M, et al.
Primary cutaneous carcinosarcoma: insights into its clonal origin and mutational pattern expression analysis through next-generation sequencing.
Hum Pathol. 2013; 44(12):2853-60 [PubMed] Related Publications
Primary cutaneous carcinosarcoma is a rare biphenotypic neoplasm exhibiting both epithelial and sarcomatous elements. Even though its origin and biological aspects remain poorly understood, it has been postulated that this tumor may arise from progenitor cells, which subsequently differentiate into distinct tumor components. We have investigated the histological and immunohistochemical staining patterns of a cutaneous carcinosarcoma case, as well as its ultrastructural aspects. In addition, sarcomatous and epithelial tumor components were separated by laser capture microdissection and subjected to targeted, high-depth, next-generation sequencing of a 46-cancer gene panel to asses the gene mutational pattern amongst both components. There were transitional cells at the epithelial/mesenchymal transition that labeled with putative progenitor cell markers (K19, c-kit, CD34 and Bcl-2). There was shared reactivity to antibodies directed against the progenitor cell marker EpCAM (epithelial cell adhesion molecule) in both components. Ultrastructurally, individual cells were demonstrated to have overlapping features of epithelial and mesenchymal differentiation. The mutational analysis revealed point mutations in exon 5 of TP53, which were identical in both the epithelial and sarcomatous components, and which were concordant with p53 expression at a tissue level. The aforementioned histological, ultrastructural, immunohistochemical and mutational pattern is strongly suggestive of a common clonal origin to the distinct elements of this tumor.

Yew KH, Crow J, Hirst J, et al.
Epimorphin-induced MET sensitizes ovarian cancer cells to platinum.
PLoS One. 2013; 8(9):e72637 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Distinctive genotypic and phenotypic features of ovarian cancer via epithelial-mesenchymal transition (EMT) have been correlated with drug resistance and disease recurrence. We investigated whether therapeutic reversal of EMT could re-sensitize ovarian cancer cells (OCCs) to existing chemotherapy. We report that epimorphin, a morphogenic protein, has pivotal control over mesenchymal versus epithelial cell lineage decision of the putative OCCs. Exposure to epimorphin induced morphological changes reminiscent of mesenchymal-to-epithelial transition (MET), but in a dose dependent manner, i.e., at 10 µg/mL of epimorphin cells obtain a more mesenchymal-like morphology while at 20 µg/mL of epimorphin cells display an epithelial morphology. The latter changes were accompanied by suppression of mesenchymal markers, such as vimentin (∼8-fold↓, p<0.02), Twist1 (∼7-fold↓, p<0.03), dystroglycan (∼4-fold↓, p<0.01) and palladin (∼3-fold↓, p<0.01). Conversely, significant elevations of KLF4 (∼28-fold↑, p<0.002), β-catenin (∼6-fold↑, p<0.004), EpCAM (∼6-fold↑, p<0.0002) and occludin (∼15-fold↑, p<0.004) mRNAs as part of the commitment to the epithelial cell lineage were detected in response to 20 µg/mL of exogenous epimorphin. Changes in occludin mRNA levels were accompanied by a parallel, albeit weaker expression at the protein level (∼5-fold↑, p<0.001). Likewise, acquisition of epithelial-like properties, including mucin1, CK19, and β-catenin gene expression, was also obtained following epimorphin treatment. Further, MMP3 production was found to be reduced whereas laminin secretion was strongly amplified upon epimorphin-induced MET. These results suggest there is a dosage window for actions of epimorphin on cellular differentiation, wherein it can either suppress or enhance epithelial differentiation of OCCs. Importantly, induction of epithelial-like phenotypes by epimorphin led to an enhanced sensitivity to carboplatin. Overall, we demonstrate that epimorphin can revert OCCs away from their mesenchymal phenotype and toward an epithelial phenotype, thereby enhancing their sensitivity to a front-line chemotherapeutic agent.

Zeng SS, Yamashita T, Kondo M, et al.
The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma.
J Hepatol. 2014; 60(1):127-34 [PubMed] Related Publications
BACKGROUND & AIMS: Recent evidence suggests that hepatocellular carcinoma can be classified into certain molecular subtypes with distinct prognoses based on the stem/maturational status of the tumor. We investigated the transcription program deregulated in hepatocellular carcinomas with stem cell features.
METHODS: Gene and protein expression profiles were obtained from 238 (analyzed by microarray), 144 (analyzed by immunohistochemistry), and 61 (analyzed by qRT-PCR) hepatocellular carcinoma cases. Activation/suppression of an identified transcription factor was used to evaluate its role in cell lines. The relationship of the transcription factor and prognosis was statistically examined.
RESULTS: The transcription factor SALL4, known to regulate stemness in embryonic and hematopoietic stem cells, was found to be activated in a hepatocellular carcinoma subtype with stem cell features. SALL4-positive hepatocellular carcinoma patients were associated with high values of serum alpha fetoprotein, high frequency of hepatitis B virus infection, and poor prognosis after surgery compared with SALL4-negative patients. Activation of SALL4 enhanced spheroid formation and invasion capacities, key characteristics of cancer stem cells, and up-regulated the hepatic stem cell markers KRT19, EPCAM, and CD44 in cell lines. Knockdown of SALL4 resulted in the down-regulation of these stem cell markers, together with attenuation of the invasion capacity. The SALL4 expression status was associated with histone deacetylase activity in cell lines, and the histone deacetylase inhibitor successfully suppressed proliferation of SALL4-positive hepatocellular carcinoma cells.
CONCLUSIONS: SALL4 is a valuable biomarker and therapeutic target for the diagnosis and treatment of hepatocellular carcinoma with stem cell features.

Govaere O, Komuta M, Berkers J, et al.
Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.
Gut. 2014; 63(4):674-85 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
OBJECTIVE: Keratin (K)19, a biliary/hepatic progenitor cell (HPC) marker, is expressed in a subset of hepatocellular carcinomas (HCC) with poor prognosis. The underlying mechanisms driving this phenotype of K19-positive HCC remain elusive.
DESIGN: Clinicopathological value of K19 was compared with EpCAM, and α-fetoprotein, in a Caucasian cohort of 242 consecutive patients (167 surgical specimens, 75 needle biopsies) with different underlying aetiologies. Using microarrays and microRNA profiling the molecular phenotype of K19-positive HCCs was identified. Clinical primary HCC samples were submitted to in vitro invasion assays and to side population analysis. HCC cell lines were transfected with synthetic siRNAs against KRT19 and submitted to invasion and cytotoxicity assays.
RESULTS: In the cohort of surgical specimens, K19 expression showed the strongest correlation with increased tumour size (p<0.01), decreased tumour differentiation (p<0.001), metastasis (p<0.05) and microvascular invasion (p<0.001). The prognostic value of K19 was also confirmed in a set of 75 needle biopsies. Profiling showed that K19-positive HCCs highly express invasion-related/metastasis-related markers (eg, VASP, TACSTD2, LAMB1, LAMC2, PDGFRA), biliary/HPC markers (eg, CD133, GSTP1, NOTCH2, JAG1) and members of the miRNA family 200 (eg, miR-141, miR-200c). In vitro, primary human K19-positive tumour cells showed increased invasiveness, and reside in the chemoresistant side population. Functionally, K19/KRT19 knockdown results in reduced invasion, loss of invadopodia formation and decreased resistance to doxorubicin, 5-fluorouracil and sorafenib.
CONCLUSIONS: Giving the distinct invasive properties, the different molecular profile and the poor prognostic outcome, K19-positive HCCs should be considered as a seperate entity of HCCs.

Sinha N, Mukhopadhyay S, Das DN, et al.
Relevance of cancer initiating/stem cells in carcinogenesis and therapy resistance in oral cancer.
Oral Oncol. 2013; 49(9):854-62 [PubMed] Related Publications
Oral squamous cell carcinoma (OSCC) acquires the top most position among the other malignancies and patients die with this disease complication within 5years. One of the causes behind this scenario is the identified sub-population in heterogeneous tumor mass that are purported as cancer stem cells (CSCs) or tumor-initiating cells (TICs). Oral CSCs populations show upregulation of the stem cell related genes Oct-4, Nanog, Nestin, CK19, BMI-1, CD117 (c-kit), CD44 and CD133 with sunken expression of involucrin and CK13. This small proportion of tumor cells can sustain tumor growth, proliferation, invasion and distant metastasis playing a pivotal role in relapse of oral cancer. Unanimous risk factors include prevalent use of cigarette smoking, tobacco chewing with less explored HPV infection play an important role in origin of CSCs. Moreover, highly apoptotic resistant oral CSCs show enhanced protective autophagy for survival. Several studies report them to be more chemo and radiation resistant than non-stem cell population implicating the failure of the present cancer therapy. This resistance associated with normal stem cell protective mechanisms including increased expression of drug efflux pumps, alteration in program cell death, cell cycle, and DNA repair mechanisms. Notably, CSCs appear to play a major role in tumor recurrence and metastatic spread, common causes of the high morbidity and ultimately the death of the majority of patients with oral cancer. In this review we would like to highlight the intricate crosstalk of the cancer initiating/stem cells involved in carcinogenesis and potential hurdle to oral cancer therapy.

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