Gene Summary

Gene:ASAH1; N-acylsphingosine amidohydrolase 1
Aliases: AC, PHP, ASAH, PHP32, ACDase, SMAPME
Summary:This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:acid ceramidase
Source:NCBIAccessed: 31 August, 2019


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 (1994-2019)
Graph generated 31 August 2019 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.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: ASAH1 (cancer-related)

Tabatabaiefar MA, Sajjadi RS, Narrei S
Epigenetics and Common Non Communicable Disease.
Adv Exp Med Biol. 2019; 1121:7-20 [PubMed] Related Publications
Common Non communicable diseases (NCDs), such as cardiovascular disease, cancer, schizophrenia, and diabetes, have become the major cause of death in the world. They result from an interaction between genetics, lifestyle and environmental factors. The prevalence of NCDs are increasing, and researchers hopes to find efficient strategies to predict, prevent and treat them. Given the role of epigenome in the etiology of NCDs, insight into epigenetic mechanisms may offer opportunities to predict, detect, and prevent disease long before its clinical onset.Epigenetic alterations are exerted through several mechanisms including: chromatin modification, DNA methylation and controlling gene expression by non-coding RNAs (ncRNAs). In this chapter, we will discuss about NCDs, with focus on cancer, diabetes and schizophrenia. Different epigenetic mechanisms, categorized into two main groups DNA methylation and chromatin modifications and non-coding RNAs, will be separately discussed for these NCDs.

Buentzel J, Yao S, Elakad O, et al.
Expression and prognostic impact of alpha thalassemia/mental retardation X-linked and death domain-associated protein in human lung cancer.
Medicine (Baltimore). 2019; 98(31):e16712 [PubMed] Related Publications
Molecular characterization of lung cancer specimens after radical surgery offers additional prognostic information and may help to guide adjuvant therapeutic procedures. The transcriptional regulators alpha thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) have recently been described in different cancer entities as a useful prognostic biomarker. This study was initiated to explore their protein expression patterns and prognostic value in patients with operable lung cancer disease.The protein abundance (in the following text also named protein expression) of ATRX and DAXX were analyzed by immunohistochemistry in 194 samples of squamous cell lung carcinoma (SQCLC), 111 samples of pulmonary adenocarcinoma (AC) and 40 samples of small cell lung cancer (SCLC). The protein levels of ATRX and DAXX were correlated with clinicopathological characteristics and patient outcome.ATRX showed strong protein expression in 16.2% of AC, 11.9% of SQCLC, and 42.5% of SCLC. DAXX was highly expressed in 54.9% of AC, 76.2% of SQCLC, and 82.5% of SCLC. Immunostaining of both ATRX and DAXX were seen in 14.4% of AC, 11.3% of SQCLC, and 42.5% of SCLC. High protein expression of ATRX was a favorable prognostic marker for patients with AC (hazard ratio 0.38, P = .02). Sub-group analyses showed a significant correlation between ATRX and the clinical stage of SQCLC and SCLC. Histological grading and ATRX were also significantly associated in cases of SQCLC.The presence of ATRX and DAXX are correlated with lung cancer histology. Strong ATRX protein expression is associated with a significantly longer overall survival in patients with AC.

Taniwaki S, Hisaka T, Sakai H, et al.
Sarcomatous Component in Pancreatic Adenosquamous Carcinoma: A Clinicopathological Series of 7 Cases.
Anticancer Res. 2019; 39(8):4575-4580 [PubMed] Related Publications
BACKGROUND/AIM: The aim of this study was to examine the clinicopathological features of pancreatic adenosquamous carcinoma (PASC).
PATIENTS AND METHODS: Our study included seven patients who underwent resection of PASC.
RESULTS: PASC is characterized by large tumors and strong infiltration into the major blood vessels and other organs, forcing many patients to undergo extended resections. In addition, all patients experienced liver metastasis recurrence following surgery, with a very poor prognosis. Histopathologically, a poorly differentiated sarcomatous component existed in all patients in addition to an adenocarcinoma component and squamous carcinoma component. Although P40 staining for the sarcomatous component was positive along with squamous carcinoma, E-cadherin expression disappeared while vimentin was expressed. It has been suggested that it is highly likely that these sarcomatous components are derived from squamous carcinoma and have an impact on prognosis.
CONCLUSION: The sarcomatous component may be related to the biological malignancy of PASC.

Fukuoka E, Yamashita K, Tanaka T, et al.
Neoadjuvant Chemotherapy Increases PD-L1 Expression and CD8
Anticancer Res. 2019; 39(8):4539-4548 [PubMed] Related Publications
BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP).
PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8
RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8
CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8

Morisaki T, Kubo M, Umebayashi M, et al.
Usefulness of the nCounter Analysis System to Monitor Immune-related Biomarkers in PBMCs During Anti-PD-1 Therapy.
Anticancer Res. 2019; 39(8):4517-4523 [PubMed] Related Publications
BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have dramatically changed the clinical outcomes of advanced tumours. However, biomarkers for monitoring immunological features during immunotherapy remain unclear, especially those in the peripheral blood, which are easily available. This study evaluated the usefulness of nCounter Analysis System in identifying immunological biomarkers in peripheral blood mononuclear cells (PBMCs) during ICI therapy.
PATIENTS AND METHODS: PBMCs from two patients who responded well to ICI therapy were used, and the expression levels of immune-related mRNA and extracellular proteins were analyzed.
RESULTS: Changes in the expression levels of 55 genes from pre-treatment to on-treatment were bioinformatically similar between the two cases. The expression levels of PD-1 were consistent with those by flow cytometry analysis, a reliable tool for monitoring various markers.
CONCLUSION: The nCounter Analysis System may be a potent tool to simultaneously investigate genes and proteins on PBMCs as biomarkers during immunotherapy using a small amount of sample.

Okuda T, Fujita M, Kato A
Significance of Elevated HMGB1 Expression in Pituitary Apoplexy.
Anticancer Res. 2019; 39(8):4491-4494 [PubMed] Related Publications
BACKGROUND/AIM: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein that exerts a range of proinflammatory actions when it is secreted extracellularly. We hypothesized that HMGB1 released from damaged cells in pituitary apoplexy would exacerbate the neurological symptoms due to acute inflammation.
PATIENTS AND METHODS: All the patients included in this study suffered from non-functioning pituitary adenoma. Four patients with apoplexy and three patients without apoplexy were included in this study. They underwent endonasal transsphenoidal endoscopic surgery to resect the tumors. We conducted enzyme-linked immunosorbent assay (ELISA) to measure HMGB1 in the surgical specimens.
RESULTS: Patients with apoplexy expressed HMGB1 at significantly higher levels than those in the non-apoplexy group (p=0.0478).
CONCLUSION: HMGB1 may be involved in subacute inflammation of pituitary apoplexy. Further work is needed to elucidate the detailed biological significance of HMGB1 in this disease.

Akashi M, Hisaka T, Sakai H, et al.
Expression of Matrix Metalloproteinases in Intraductal Papillary Mucinous Neoplasm of the Pancreas.
Anticancer Res. 2019; 39(8):4485-4490 [PubMed] Related Publications
BACKGROUND/AIM: Intraductal papillary mucinous neoplasm (IPMN) has a variety of histological and morphological appearances. Matrix metalloproteinases (MMPs) have been considered to be associated with tumor progression or poor prognosis. The aim of this study was to elucidate the molecular basis of IPMN variation in different types of lesions.
MATERIALS AND METHODS: The expression of MMP-1,2,7,9 in 51 cases of IPMN were investigated. The MMP score was calculated as the sum of the score of staining distribution and the score of the intensity staining.
RESULTS: MMP scores were correlated with histological grade, histological subtype, and type of invasion. MMP high expression groups (MMP score ≥5) had worse prognosis than low-expression groups.
CONCLUSION: MMP expression varied between different types of IPMN, a result supporting differences in molecular basis of malignancies. These considerations may be helpful for optimal management or treatment according to various types of IPMN.

Honda T, Inagawa H
Usefulness of Monocytes/macrophages Activated With Low-dose Lipopolysaccharide in Tumor Tissue and Adipose Tissue of Obesity.
Anticancer Res. 2019; 39(8):4475-4478 [PubMed] Related Publications
Chronic inflammation is involved in the development of cancer, lifestyle-related diseases, and autoimmune diseases. It also influences the severity of these diseases. Macrophages that accumulate in tumor tissues and adipose tissues of obesity have been shown to increase expression of inflammatory cytokines, thereby inducing inflammatory changes in these tissues. The macrophage phenotype is believed to be important in mediating inflammatory changes in tissues. Recently, monocytes/macrophages activated with low-dose lipopolysaccharide (LPS) were demonstrated to suppress increased expression of monocyte chemotactic protein (MCP)-1 and inflammatory cytokines (interleukin (IL)-1 β, IL-8, and tumor necrosis factor (TNF)-α). By suppressing the increased expression of chemotaxis-related and inflammation-related factors, monocytes/macrophages activated with low-dose LPS are considered to suppress the migration of macrophages into tissues and to regulate inflammatory changes in these tissues, respectively. The effects of macrophages activated with low-dose LPS were different from those of macrophages activated with high-dose LPS. In this review, we discuss the usefulness of monocytes/macrophages activation by low-dose LPS.

Amisaki M, Yagyu T, Uchinaka EI, et al.
Prognostic Value of DEPDC1 Expression in Tumor and Non-tumor Tissue of Patients With Hepatocellular Carcinoma.
Anticancer Res. 2019; 39(8):4423-4430 [PubMed] Related Publications
BACKGROUND/AIM: To evaluate the impact of DEPDC1 expression on patient prognosis after hepatic resection for hepatocellular carcinoma (HCC).
PATIENTS AND METHODS: We reviewed data from 75 patients who underwent hepatic resection for HCC between 2004 and 2013. Recurrence at 2 years following resection, which mainly included metastatic recurrence, was defined as late recurrence.
RESULTS: DEPDC1 was up-regulated in HCC tissue and in non-tumor tissue of patients with HCC compared to normal liver (p<0.01 and p<0.01, respectively). High expression of DEPDC1 was associated with poor overall, disease-specific, and disease-free survival (p=0.02, p<0.01, and p<0.01, respectively). High DEPDC1 expression was an independent predictor of death and recurrence (p=0.03 and p<0.01, respectively). High expression of DEPDC1 in non-tumor liver was an independent risk factor for late recurrence (p=0.04).
CONCLUSION: High expression of DEPDC1 in tumor tissue appears to be associated with tumor progression and poor prognosis.

Ashizawa N, Shimizu H, Sudo M, et al.
Clinical Significance of NADPH Oxidase 5 in Human Colon Cancer.
Anticancer Res. 2019; 39(8):4405-4410 [PubMed] Related Publications
BACKGROUND/AIM: Recent studies have reported the involvement of NADPH oxidases (NOXs) in tumor progression. However, the role of NOX5 in colon cancer is unclear. We examined the clinical significance of NOX5 expression in colon cancer.
PATIENTS AND METHODS: NOX5 expression was evaluated by immunohistochemistry in 119 patients with stage II or III colon cancer, and the relationship between NOX5 expression and clinicopathological data was analyzed.
RESULTS: Of all tissues, 39.5% were negative and 60.5% were positive for NOX5 expression. Positive expression was significantly associated with undifferentiated histology (p=0.037) and lymph node metastasis (p=0.023). The 5-year progression-free survival rate of NOX5-positive patients was significantly worse than that of NOX5-negative patients (p=0.046). The rates of local recurrence observed in NOX5-positive patients were higher than that in NOX5-negative patients.
CONCLUSION: NOX5 expression may be related to poor prognostic factors and could be useful as a prognostic biomarker.

Itoh M, Okuhashi Y, Takahashi Y, et al.
Hypoxia Up-regulates HIF Expression While Suppressing Cell Growth and NOTCH Activity in Leukaemia Cells.
Anticancer Res. 2019; 39(8):4165-4170 [PubMed] Related Publications
AIM: To examine the influence of hypoxia on the in vitro growth of leukaemia cells and the activity of signalling proteins to better understand the pathophysiology of leukaemia cells in human bone marrow.
MATERIALS AND METHODS: Six human leukaemia cell lines were cultured under normoxic or hypoxic conditions. Cell growth, recovery of clonogenic cells, and the expression and activation of various signalling proteins were examined.
RESULTS: Hypoxia suppressed cell growth and the recovery of clonogenic cells. Moreover, hypoxia up-regulated hypoxia-inducible factor (HIF) 1α and HIF2α expression while suppressing the expression and activation of NOTCH1, mechanistic target of rapamycin kinase (mTOR) activation, and nuclear factor-kappa B (NF-κB) phosphorylation.
CONCLUSION: We found that hypoxia up-regulated HIF expression while it suppressed the self-renewal capacity of leukaemia cells, NOTCH activity, and expression of its down-stream signalling molecules, which differs from previous reports mentioning that HIF activates NOTCH signalling. Our findings serve to further elucidate the in vivo pathophysiology of leukaemia cells.

Nishizawa Y, Ikeda R, Yamamoto M, et al.
5-Aza-2-deoxycytidine Enhances the Sensitivity of 5-Fluorouracil by Demethylation of the Thymidine Phosphorylase Promoter.
Anticancer Res. 2019; 39(8):4129-4136 [PubMed] Related Publications
BACKGROUND/AIM: 5-Aza-2-deoxycytidine (5-Aza-CdR) enhances the sensitivity to 5-fluorouracil (5-FU), but the molecular mechanism is not fully understood. The aim of this study was to investigate the molecular mechanism that enhances the sensitivity to 5-FU treated with 5-Aza-CdR via thymidine phosphorylase (TP).
MATERIALS AND METHODS: The sensitivity to drugs was determined on several cancer cell lines by the MTT assay. Protein and mRNA levels were examined by immunoblot and RT-PCR, respectively. Gene silencing, binding of Sp1 to DNA and methylation of DNA was performed by siRNA, ChIP assay and sodium bisulfate genomic sequencing, respectively.
RESULTS: Sp1-binding sites in the TP promoter were methylated in epidermoid carcinoma. 5-Aza-CdR demethylated Sp1-binding sites and enhanced sensitivity to 5-FU.
CONCLUSION: Demethylation of Sp1-binding sites by 5-Aza-CdR was a key factor enhancing 5-FU sensitivity, which may enable more effective treatments for cancer patients with the combination of 5-Aza-CdR and 5-FU.

Nakazawa N, Ogata K, Yokobori T, et al.
Low IRBIT Levels Are Associated With Chemo-resistance in Gastric Cancer Patients.
Anticancer Res. 2019; 39(8):4111-4116 [PubMed] Related Publications
BACKGROUND/AIM: We investigated whether the expression of inositol 1, 4, 5-trisphosphate receptor-binding protein released with inositol 1, 4, 5-trisphosphate (IRBIT) in clinical gastric cancer (GC) patients could predict the therapeutic response to postoperative adjuvant chemotherapy.
MATERIALS AND METHODS: Immunohistochemistry was used to investigate IRBIT expression in 115 GC patients. To clarify whether IRBIT had a relationship with the therapeutic effects of chemotherapy, we compared two groups - 62 patients treated with postoperative adjuvant chemotherapy and 53 patients treated with postoperative adjuvant chemotherapy.
RESULTS: Regarding the postoperative adjuvant chemotherapy-free group, we did not find any statistically significant correlation between clinicopathological features and recurrence regardless of the expression of IRBIT. In contrast, in the group receiving postoperative adjuvant chemotherapy, a significant association was found between IRBIT expression and both overall and disease-free survival.
CONCLUSION: IRBIT may be used as a useful predictive marker for chemotherapy.

Matsunaga N, Wakasaki T, Yasumatsu R, Kotake Y
Long Noncoding RNA,
Anticancer Res. 2019; 39(8):4073-4077 [PubMed] Related Publications
BACKGROUND/AIM: ANRIL is a long noncoding RNA located on INK4 locus, which encodes p15 and p16 that cause G
MATERIALS AND METHODS: Cells were transfected with siRNA oligonucleotides targeting ANRIL. Transfected cells were subjected to cell-cycle and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis.
RESULTS: Depletion of ANRIL increased p15 mRNA in FaDu cells, and p15 and p16 mRNA in CAL27 cells and inhibited proliferation of these cells. Cell cycle analysis showed that depletion of ANRIL caused arrest at the G

Kang BW, Baek DW, Kang H, et al.
Novel Therapeutic Approaches for Epstein-Barr Virus Associated Gastric Cancer.
Anticancer Res. 2019; 39(8):4003-4010 [PubMed] Related Publications
Epstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is classified as one of four GC subtypes by comprehensive molecular characterization. Though the mechanism of tumorigenesis by EBV infection has not yet been fully clarified, EBV infection might contribute to the malignant transformation of GC cells by involving various cellular processes and signaling pathways. EBVaGC has shown the following distinct characteristics in contrast to other subtypes: extreme DNA hypermethylation, recurrent phosphatidylinositol 4,5-biphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) mutations, overexpression of programmed cell death ligand 1/2 (PD-L1/2), and occasional immune cell signaling activation. Therefore, using these molecular features as guides, targeted agents need to be evaluated in clinical trials for EBVaGC. Accordingly, this review uses the best available evidence to focus on novel therapeutic approaches using the distinct pathologic characteristics of EBVaGC patients.

Xu L, Wu Q, Zhou X, et al.
TRIM13 inhibited cell proliferation and induced cell apoptosis by regulating NF-κB pathway in non-small-cell lung carcinoma cells.
Gene. 2019; 715:144015 [PubMed] Related Publications
Tripartite Motif Containing 13 (TRIM13), a member of TRIM proteins, is deleted in multiple tumor types, especially in B-cell chronic lymphocytic leukemia and multiple myeloma. The present study explored the expression and potential role of TRIM13 in non-small-cell lung carcinoma (NSCLC). We found that TRIM13 mRNA and protein expression was reduced in NSCLC tissues and cell lines in comparison to paired non-cancerous tissues and a human normal bronchial epithelial cell line, respectively. Overexpression of TRIM13 in NCI-H1975 and SPC-A-1 cells hampered cell proliferation. Additionally, TRIM13 overexpression increased the levels of cleaved caspase-3. TRIM13-induced NSCLC cell apoptosis was attenuated by a caspase-3 inhibitor Ac-DEVD-CHO, suggesting that TRIM13 induced cell apoptosis partially through a caspase-3-dependent pathway. Moreover, it has been reported that TRIM13 can regulate nuclear factor kappaB (NF-κB) activity. Our data showed that TRIM13 overexpression inactivated NF-κB as indicated by the increased cytosolic NF-κB and decreased nuclear NF-κB. Exposure to an NF-κB inhibitor PDTC significantly blocked the impact of TRIM13 knockdown on cell proliferation and apoptosis, indicating the functions of TRIM13 in NSCLC cells were mediated by the NF-κB pathway. Finally, we demonstrated that TRIM13 overexpression suppressed tumor growth and induced cell apoptosis in vivo by using a xenograft mouse model. Collectively, our results indicate that TRIM13 behaves as a tumor suppressor in NSCLC through regulating NF-κB pathway. Our findings may offer a promising therapeutic target for NSCLC.

Vakili Saatloo M, Aghbali AA, Koohsoltani M, Yari Khosroushahi A
Akt1 and Jak1 siRNA based silencing effects on the proliferation and apoptosis in head and neck squamous cell carcinoma.
Gene. 2019; 714:143997 [PubMed] Related Publications
Based on Akt1 and Jak1 key roles in apoptosis and proliferation of many cancers, the aim of this study was to find a new gene therapy strategy by silencing of these main anti-apoptotic genes for HNSCC treatment. Cancerous HN5 and normal HUVEC cell lines were treated with Akt1 and Jak1 siRNAs alone or with each other combined with/without cisplatin. The MTS, flow cytometry, 4',6-diamidino-2-phenylindole staining, real-time PCR and ELISA methods were utilized in this study. The highest percentage of apoptosis was observed in the treatment of Jak1 siRNA/cisplatin group in cancerous HN5 cells (96.5%) where this treatment showed 12.84% apoptosis in normal HUVEC cell line. Cell viability reduced significantly to 64.57% after treatment with Akt1 siRNA in HN5 treated group. Knocking down Akt1 and Jak1 genes using siRNAs could increase levels of apoptosis and reduce proliferation rate in HNSCC indicating the powerful effects of these genes siRNAs with or without chemotherapeutic agents in HNSCC treatment. In conclusion, the combination of siRNA-mediated gene-silencing strategy can be considered as a valuable and safe approach for sensitizing cancer cells to chemotherapeutic agents thus proposed further studies regarding this issue to approve some siRNA based therapeutics for using in clinic.

Naghizadeh S, Mohammadi A, Baradaran B, Mansoori B
Overcoming multiple drug resistance in lung cancer using siRNA targeted therapy.
Gene. 2019; 714:143972 [PubMed] Related Publications
Among cancers, lung cancer is the most morbidity and mortality disease that is remaining the fatalist. Generally, there are multiple treatment procedures for lung cancer, such as surgery, immunotherapy, radiotherapy and chemotherapy. There is, therefore, an urgent need for more specified and efficient methods for treatment of lung cancer such as RNAi, which in combination with traditional therapies could silence genes that are involved in the drug resistance. These genes may either be motivators of apoptosis inhibition, EMT and DNA repair system promoters or a member of intracellular signaling pathways, such as JAK/STAT, RAS/RAF/MEK, PI3K/AKT, NICD, B-catenin/TCF/LEF and their stimulator receptors including IGFR, EGFR, FGFR, VEGFR, CXCR4, MET, INTEGRINS, NOTCH1 and FRIZZLED, so could be considered as appropriate targets. In current review, the results of multiple studies which have employed drug application after one specific gene silencing or more than one gene from distinct pathways also simultaneous drug and RNAi usage in vitro and in vivo in lung cancer were summarized.

Banerjee S, Karunagaran D
An integrated approach for mining precise RNA-based cervical cancer staging biomarkers.
Gene. 2019; 712:143961 [PubMed] Related Publications
Since international federation of gynecology and obstetrics (FIGO) staging is mainly based on clinical assessment, an integrated approach for mining RNA based biomarkers for understanding the molecular deregulation of signaling pathways and RNAs in cervical cancer was proposed in this study. Publicly available data were mined for identifying significant RNAs after patient staging. Significant miRNA families were identified from mRNA-miRNA and lncRNA-miRNA interaction network analyses followed by stage specific mRNA-miRNA-lncRNA association network generation. Integrated bioinformatic analyses of selected mRNAs and lncRNAs were performed. Results suggest that HBA1, HBA2, HBB, SLC2A1, CXCL10 (stage I), PKIA (stage III) and S100A7 (stage IV) were important. miRNA family enrichment of interacting miRNA partners of selected RNAs indicated the enrichment of let-7 family. Assembly of collagen fibrils and other multimeric structures_Homosapiens_R-HSA-2022090 in pathway analysis and progesterone_CTD_00006624 in DSigDB analysis were the most significant and SLC2A1, hsa-miR-188-3p, hsa-miR-378a-3p and hsa-miR-150-5p were selected as survival markers.

Fasihi A, Soltani BM, Ranjbaran ZS, et al.
Hsa-miR-942 fingerprint in colorectal cancer through Wnt signaling pathway.
Gene. 2019; 712:143958 [PubMed] Related Publications
The Wnt signaling pathway has been identified for its function in carcinogenesis and embryonic development. It is known to play a vital role in the initiation and development of colorectal cancer (CRC). Therefore, it is of great importance for CRC research to illuminate the mechanisms which regulate Wnt pathway activity. Here, we intended to examine the effect of hsa-miR-942 (miR-942) on the Wnt signaling activity, cell cycle progression, and its expression in CRC tissues. RT-qPCR results indicated that miR-942 is significantly upregulated in colorectal cancer. Then, overexpression of miR-942 promoted, whereas its inhibition decreased the Wnt signaling activity, detected by RT-qPCR and Top/Fop flash assay. Inhibition of Wnt signaling by using PNU-74654 or IWP-2 small molecules indicated that miR-942 applies its effect to the β-catenin degradation complex level. Then, RT-qPCR and dual luciferase assay showed that miR-942 upregulated Wnt signaling through direct targeting of APC, which is a tumor suppressor in Wnt signaling pathway. Furthermore, the western blotting analysis indicated that β.catenin, as a main member of Wnt signaling pathway is upregulated following the overexpression of miR-942. Finally, miR-942 overexpression resulted in cell cycle progression in SW480 cells. Taken together, our findings established an oncogenic role for miR-942 in CRC and indicated that this miRNA might be a crucial target for CRC therapy.

Silva OB, Correia NAA, de Barros FT, et al.
3' untranslated region A>C (rs3212227) polymorphism of Interleukin 12B gene as a potential risk factor for Hodgkin's lymphoma in Brazilian children and adolescents.
Tumour Biol. 2019; 41(7):1010428319860400 [PubMed] Related Publications
Interleukin 12 plays an important role in immunoregulation between the T helper 1/T helper 2 lymphocytes and in the antiviral and antitumor immune response. The aim of this study was to investigate the possible association between the interleukin 12B polymorphism rs3212227 and the risk to develop Hodgkin's lymphoma in childhood and adolescents. A total of 100 patients with Hodgkin's lymphoma and a group of 181 healthy controls were selected at random from a forensic laboratory of the University of Pernambuco. The AA genotype was detected in the controls (53.04%) and the AC genotype was found in the patients (54%). The AC genotype showed an association with the development of Hodgkin's lymphoma (odds ratio = 2.091, 95% confidence interval = 1.240-3.523, p = 0.007). When AC + CC genotypes were analyzed together, an increase in risk of 1.9 times more chances for HL development could be observed (odds ratio = 1.923, 95% confidence interval = 1.166-3.170, p = 0.014). However, there was no association between the AC and CC genotypes of the interleukin 12B polymorphism with the clinical risk group (p = 0.992, p = 0.648, respectively). Our results suggest that the presence of the C allele may be contributing to the development of Hodgkin's lymphoma in children and adolescents.

Maehana S, Matsumoto Y, Kojima F, Kitasato H
Interleukin-24 Transduction Modulates Human Prostate Cancer Malignancy Mediated by Regulation of Anchorage Dependence.
Anticancer Res. 2019; 39(7):3719-3725 [PubMed] Related Publications
BACKGROUND: Hormone therapy and chemotherapy are not effective for castrate-resistant prostate cancer, thus development of novel treatment strategies is required. Gene therapy involving transient high-copy transfection of interleukin (IL)-24 with an adenoviral vector can exert antitumor activity; however, the effects of stable IL-24 transfection are not fully understood. The aim of this study was to investigate the effects of IL-24 overexpression in prostate cancer cells, in vitro.
MATERIALS AND METHODS: DU145 cells were transfected the IL-24 gene using a retroviral vector. Apoptosis induction was investigated by the cell death detection ELISA, and the gene expression was analyzed by real time RT-PCR.
RESULTS: IL-24 transduction suppressed the growth of prostate cancer and induced tumor cell apoptosis. In addition, up-regulation of epithelial markers and down-regulation of mesenchymal markers were noted, suggesting that tumor aggressiveness was reduced.
CONCLUSION: Introduction of IL-24 displays antitumor activity both by induction of apoptosis and regulation of anchorage dependence.

Liu Y, Kwon T, Kim JS, et al.
Peroxiredoxin V Reduces β-Lapachone-induced Apoptosis of Colon Cancer Cells.
Anticancer Res. 2019; 39(7):3677-3686 [PubMed] Related Publications
BACKGROUND/AIM: Peroxiredoxin (Prx) V has been known as an antioxidant enzyme which scavenges intracellular reactive oxygen species (ROS). Also, Prx V has been shown to mediate cell apoptosis in various cancers. However, the mechanism of Prx V-induced apoptosis in colon cancer cells remains unknown. Thus, in this study we analyzed the effects of Prx V in β-lapachone-induced apoptosis in SW480 human colon cancer cells.
MATERIALS AND METHODS: β-lapachone-induced apoptosis was analyzed by the MTT assay, western blotting, fluorescence microscopy, Annexin V staining and flow cytometry.
RESULTS: Overexpression of Prx V, significantly decreased β-lapachone-induced cellular apoptosis and Prx V silencing increased β-lapachone-induced cellular apoptosis via modulating ROS scavenging activity compared to mock SW480 cells. In addition, to further explore the mechanism of Prx V regulated β-lapachone-induced SW480 cells apoptosis, the Wnt/β-catenin signaling was studied. The Wnt/ β-catenin signaling pathway was found to be induced by β-lapachone.
CONCLUSION: Prx V regulates SW480 cell apoptosis via scavenging ROS cellular levels and mediating the Wnt/β-catenin signaling pathway, which was induced by β-lapachone.

Wu MR, Nissim L, Stupp D, et al.
A high-throughput screening and computation platform for identifying synthetic promoters with enhanced cell-state specificity (SPECS).
Nat Commun. 2019; 10(1):2880 [PubMed] Free Access to Full Article Related Publications
Cell state-specific promoters constitute essential tools for basic research and biotechnology because they activate gene expression only under certain biological conditions. Synthetic Promoters with Enhanced Cell-State Specificity (SPECS) can be superior to native ones, but the design of such promoters is challenging and frequently requires gene regulation or transcriptome knowledge that is not readily available. Here, to overcome this challenge, we use a next-generation sequencing approach combined with machine learning to screen a synthetic promoter library with 6107 designs for high-performance SPECS for potentially any cell state. We demonstrate the identification of multiple SPECS that exhibit distinct spatiotemporal activity during the programmed differentiation of induced pluripotent stem cells (iPSCs), as well as SPECS for breast cancer and glioblastoma stem-like cells. We anticipate that this approach could be used to create SPECS for gene therapies that are activated in specific cell states, as well as to study natural transcriptional regulatory networks.

Barajas-Olmos FM, Ortiz-Sánchez E, Imaz-Rosshandler I, et al.
Analysis of the dynamic aberrant landscape of DNA methylation and gene expression during arsenic-induced cell transformation.
Gene. 2019; 711:143941 [PubMed] Related Publications
Inorganic arsenic is a well-known carcinogen associated with several types of cancer, but the mechanisms involved in arsenic-induced carcinogenesis are not fully understood. Recent evidence points to epigenetic dysregulation as an important mechanism in this process; however, the effects of epigenetic alterations in gene expression have not been explored in depth. Using microarray data and applying a multivariate clustering analysis in a Gaussian mixture model, we describe the alterations in DNA methylation around the promoter region and the impact on gene expression in HaCaT cells during the transformation process caused by chronic exposure to arsenic. Using this clustering approach, the genes were grouped according to their methylation and expression status in the epigenetic landscape, and the changes that occurred during the cellular transformation were identified adequately. Thus, we present a valuable method for identifying epigenomic dysregulation.

Kishore C, Sundaram S, Karunagaran D
Vitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.
Chem Biol Interact. 2019; 309:108725 [PubMed] Related Publications
Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as β-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.

Yoo SK, Song YS, Lee EK, et al.
Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer.
Nat Commun. 2019; 10(1):2764 [PubMed] Free Access to Full Article Related Publications
Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAF

Jin N, Bi A, Lan X, et al.
Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer.
Nat Commun. 2019; 10(1):2701 [PubMed] Free Access to Full Article Related Publications
One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies.

Yarahmadi S, Abdolvahabi Z, Hesari Z, et al.
Inhibition of sirtuin 1 deacetylase by miR-211-5p provides a mechanism for the induction of cell death in breast cancer cells.
Gene. 2019; 711:143939 [PubMed] Related Publications
Sirtuin 1 is one of the regulators of cell growth and survival and its inhibition is suggested as a suitable mechanism to overcome breast cancer development. In this study we explored the role of miR-211-5p in SIRT1/p53 pathway and its influence on breast cancer cell viability and apoptosis. Cells were transfected with miR-211-5p mimic and inhibitor to modulate cellular miR-211-5p levels in breast cancer cell lines, MDA-MB-231 and MCF-7. Gene expression of miR-211-5p and SIRT1 were measured with real-time PCR. SIRT1 protein level and the acetylation of p53 as well as SIRT1 activity were evaluated by Western blotting and fluorometry, respectively. In order to explore the direct attachment of miR-211-5p to the 3'-UTR of SIRT1 mRNA, luciferase reporter assay was applied. Cell viability in response to miR-211-5p was studied by MTT assay and apoptosis was assessed by annexin V labeling followed by flow cytometry. Results showed that SIRT1 gene and protein expression were inhibited by miR-211-5p and the 3'-UTR of SIRT1 was found to be directly targeted by miR-211-5p. Inhibition of SIRT1 expression resulted in its reduced activity. Up-regulation of miR-211-5p was also followed by a significant decline in the acetylation status of p53 which was associated with remarkable decreased cell viability and induction of apoptosis in breast cancer cells. Antisense oligonucleotide of miR-211-5p acted as its inhibitor and exerted opposite effects both on SIRT1 expression and cell apoptosis. In conclusion, inhibition of SIRT1 by miR-211-5p could effectively reduce breast cancer cell survival and cause cell death and therefore might be considered a seemly mechanism for designing anticancer therapies.

Rahimi Babasheikhali S, Rahgozar S, Mohammadi M
Ginger extract has anti-leukemia and anti-drug resistant effects on malignant cells.
J Cancer Res Clin Oncol. 2019; 145(8):1987-1998 [PubMed] Related Publications
PURPOSE: Based on the poor prognosis of drug resistance in pediatric acute lymphoblastic leukemia (ALL) and adverse effects of chemotherapy, this study was aimed to evaluate the effect of several herbal extracts on leukemic cells.
METHODS: Two subtypes of T- and B-ALL cell lines, followed by ALL primary cells were treated with cinnamon, ginger, and green tea extracts, alone or in combination with methotrexate (MTX). Possible apoptosis was investigated using Annexin-V/PI double staining. Real-time PCR was applied to evaluate the expression levels of related ABC transporters upon combination therapy.
CONCLUSION: To the best of our knowledge, this is the first study that reveals the antileukemic effect of ginger extract on both, pediatric ALL cell lines and primary cells.

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