MARVELD1 inhibited cell proliferation and enhance chemosensitivity via increasing expression of p53 and p16 in hepatocellular carcinoma

Abstract

We have previously found that expression of MARVELD1 was remarkably downregulated in multiple tumor tissues, but unclear in hepatocellular carcinoma (HCC) and its function has not been explored yet. In the present study, to uncover the underlying mechanism of MARVELD1 in the pathogenesis and development of HCC, we investigated the expression pattern of MARVELD1 and its effect on tumor proliferation in HCC. The results indicated the frequent downregulation of MARVELD1 in clinic samples and cell lines of HCC resulted from promoter methylation, as well as genetic deletion. Furthermore, treatment of MARVELD1 unexpressing Hep3B2.1-7 and PLC/PRF/5 cells with the demethylating agent 5-aza-2′ deoxycytidine restored its expression. Overexpression of MARVELD1 suppressed the proliferation of HCC cells in vitro and in vivo, whereas downregulation of endogenous MARVELD1 by shRNAs significantly enhanced these characters. MARVELD1 overexpression could enhance chemosensitivity of HCC cells to epirubicin and 10-hydroxycamptothecin. Corresponding to these results, the expression of p-ERK1/2 and cyclin D1 were decreased, whereas p16 and p53 were increased in MAR-VELD1-transfected cells. We also demonstrated that knockdown of MARVELD1 resulted in upregulation of p-ERK1/2 and cyclin D1, and downregulation of p16 and p53. Moreover, the effect of the decreased cell growth rate was significantly reversed when MAR-VELD1-overexpressing cells were trasfected with p53 or p16 siR-NA. Our findings suggest that MARVELD1 is a tumor suppressor by negatively regulating proliferation, tumor growth and chemosensitivity of HCC cells via increasing p53 and p16 in vitro and in vivo. MARVELD1 may be a potential target for HCC therapy. (Cancer Sci 2012; 103: 716-722) H epatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, and its incidence is still rising.(1) Currently there are about 600 000 cases of HCC each year, and nearly 78% of them are from Asian countries.(2) Substantial evidence from epidemiological studies indicates that HCC is strongly associated with alcohol abuse, chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and liver cirrhosis.(3-5) More than one million people die of liver cancer worldwide every year.(6) Few patients are diagnosed in the early stage, and <20% of HCCs can be resected completely. (7,8) Resistance to many of chemotherapy agents is a major obstacle to successful HCC treatment.(9-11) Therefore, a better understanding of the molecular mechanisms underlying HCC progression is urgently needed for leading to a more effective treatment.Genetic and epigenetic aberrations, leading to the activation of oncogenes and inactivation of tumor suppressor genes, are thought to play major roles in the pathogenesis of HCC. Recently, several MARVEL (proteins of the myelin and lymphocytes [MAL] and related proteins for vesicle trafficking and membrane link) domain-containing proteins have attracted increasing interest because they exhibit tumor suppressor activities a...

Inhibition of SREBP increases gefitinib sensitivity in non-small cell lung cancer cells

“…However, it has been reported that overexpression of MARVELD1 promotes the tumor sensitivity to chemotherapy in hepatocellular carcinoma, and our results seems conflicted with previous study [10]. To clarify this, we assessed the sensitivity of A549 cells to a serial chemo-drugs by overexpression of MARVELD1.…”

“…MARVELD1 is previously reported as a drug-resistant related protein [10]. Here, we validated the interaction between SREBP and MARVELD1 by co-immunoprecipitation (Figure 2A).…”

MARVELD1 Inhibits Nonsense-Mediated RNA Decay by Repressing Serine Phosphorylation of UPF1

“…To deplete the expression of MARVELD1 and UPF1, the siRNAs were used as follows: siMARVELD1 5’-r(AUU GGA ACC AGG CUU CUG G)-3’ [9], siMARVELD1-2 5’-r(CCU CAA GGA UUA CCC GCU C)-3’, siUPF1-1 5’-r(GAU GCA GUU CCG CUC CAU U)-3’ [15] and siUPF1-2 5’-r(GAG AAU CGC CUA CUU CAC U)-3’ [16]. …”

“…We previously reported that MARVELD1 localized to interphase cell nuclei and was downregulated in multiple tumor tissues [8]. The overexpression of MARVELD1 inhibited proliferation and enhanced chemosensitivity in hepatocellular carcinoma cells [9]. We also identified the interaction between MARVELD1 and importin β1 by liquid chromatography-tandem mass spectrometry analysis and coimmunoprecipitation in HeLa cells [10].…”

Identifying differential expression genes and single nucleotide variations using RNA-seq in metastatic melanoma

“…Zeng et al (2011) examined the function of MARVELD1 in mice and demonstrated that overexpression of mouse MARVELD1 inhibited cell proliferation, G1-phase arrest, and cell migration. In hepatocellular carcinoma, MARVELD1 is a tumor suppressor that regulates tumor growth and may be a potential biomarker for hepatocellular carcinoma therapy (Yu et al, 2012).…”