MAL gene expression in esophageal cancer suppresses motility, invasion and tumorigenicity and enhances apoptosis through the Fas pathway

Mimori, Koshi; Shiraishi, Takeshi; Mashino, Kohjiro; Sonoda, Hideto; Yamashita, Keishi; Yoshinaga, Keiji; Masuda, Takaaki; Utsunomiya, Tohru; Alonso, Miguel A.; Inoue, Hiroshi; Mori, Masaki

doi:10.1038/sj.onc.1206378

Cited by 79 publications

(85 citation statements)

References 27 publications

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“…They are involved in a variety of biological processes, including cell cycle progression, chemotactic activity, tight junction, and clathrin-mediated endocytosis. (15,(18)(19)(20) It is documented that MARVEL domain-containing proteins are decreased in various types of cancer, and exert tumor-suppressive functions. (12)(13)(14)(15) MARVELD1 is a novel member of this family, with very limited work performed so far about its molecular function.…”

Section: Discussionmentioning

confidence: 99%

“…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 and are frequently decreased via promoter methylation in breast, cervical, prostate, hepatocellular, esophageal and gastric carcinoma or cell lines. (12)(13)(14)(15) MARVELD1 is a member of MARVEL domain-containing proteins, located on human chromosome 10q24, a locus associate with multiple cancers. Our previous study shows that MARVELD1 is frequently downregulated in multiple cancers.…”

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

Zhang

et al. 2012

Cancer Science

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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...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Zhang

et al. 2012

Cancer Science

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“…Biomarkers can be used to predict prognosis and optimise therapeutic strategies. Hypermethylation of the MAL promoter has been shown in colorectal and oesophageal cancers and MAL has been proposed as a putative tumour suppressor in these cancer types (Mimori et al, 2003;Kazemi-Noureini et al, 2004;Mori et al, 2006). Moreover, it has been proposed as a candidate marker for early detection of these cancers, as methylation of MAL could already be detected in precursor lesions (Lind et al, 2007(Lind et al, , 2008Mimori et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In other gastrointestinal cancers, that is, colorectal and oesophageal cancer, the T-lymphocyte maturation associated protein MAL, involved in glycolipid-enriched membrane-mediated apical transport, has been described to be inactivated by promoter hypermethylation (Puertollano and Alonso, 1999;Mimori et al, 2003;Kazemi-Noureini et al, 2004;Mori et al, 2006;Lind et al, 2007). Promoter hypermethylation of MAL was a frequent event in these two cancer types, but infrequent in normal mucosa.…”

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MAL promoter hypermethylation as a novel prognostic marker in gastric cancer

et al. 2008

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T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT -PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P ¼ 0.03) and multivariate analysis (P ¼ 0.03) and with downregulation of expression (P ¼ 0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker.

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“…Recently, downregulation of MAL has been associated with a variety of human epithelial malignancies. For example, Mimori et al (7) initially found that MAL was highly expressed in normal esophageal epithelia, but silenced in esophageal tumors. Later, inactivation of MAL was shown to be a common event in breast, head and neck, and gastric cancer (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Suppression of MAL gene expression is associated with colorectal cancer metastasis

2015

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Abstract. Mal, T-cell differentiation protein (MAL) is a candidate tumor suppressor gene that functions in membrane trafficking processes in polarized epithelial cells. The aim of the present study was to determine its clinical significance in colorectal cancer (CRC). The RNA and protein expression levels of MAL in 30 colorectal specimens were detected by semi-quantitative polymerase chain reaction and immunohistochemistry analysis. Statistical analysis was performed using SPSS software. The RNA level of MAL was significantly downregulated in the CRC tissues compared with the adjacent healthy tissue (P<0.05). MAL was only positively expressed in 20% of the CRC tissues, but in 66.7% of the adjacent tissues, as determined by immunohistochemistry analysis. The expression of the MAL RNA transcript exhibited a positive correlation with protein expression. The expression levels of MAL were significantly associated with different tumor-node-metastasis stages and lymph node metastasis (P<0.05), but not with age, gender, tumor site, differentiation status and pathological type (P>0.05). Suppression of MAL expression was significantly correlated with metastasis in CRC. The present study indicated that MAL may function as an anti-metastasis factor and represent a potential biomarker for malignant colorectal tumors. IntroductionColorectal cancer (CRC) is the third most common malignant cancer and the second leading cause of mortality worldwide (1). In China, the incidence rate of CRC is increasing rapidly, particular in urban areas, such as Shanghai, which was formerly considered a low-risk area (2,3). Metastasis is the main cause of mortality in CRC patients (4). The first sites of metastatic CRC are the regional lymph nodes and the liver. Investigations into the molecular mechanisms involved in CRC metastasis are of major importance in order to develop novel strategies for targeted therapies (5).The mal, T-cell differentiation protein (MAL) gene encodes the T-lymphocyte maturation-associated protein and functions in T-cell differentiation (6). Recently, downregulation of MAL has been associated with a variety of human epithelial malignancies. For example, Mimori et al (7) initially found that MAL was highly expressed in normal esophageal epithelia, but silenced in esophageal tumors. Later, inactivation of MAL was shown to be a common event in breast, head and neck, and gastric cancer (8-11). However, the functional role and mechanistic action of MAL in CRC remains largely unknown. The present study aimed to determine the clinical significance of MAL in colorectal cancer by measuring its expression level in CRC tissues. Materials and methodsTissue samples and cell line. The present study enrolled a total of 30 CRC patients who underwent surgery between 2010 and 2011 at Shanghai First People's Hospital (Shanghai, China). The patients did not receive any pre-operative cancer treatment prior to resection. Of the 30 patients, 18 were male and 22 were female, and the age of the patients ranged between 45 and 87 years (median, 6...

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MAL gene expression in esophageal cancer suppresses motility, invasion and tumorigenicity and enhances apoptosis through the Fas pathway

Cited by 79 publications

References 27 publications

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

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

MAL promoter hypermethylation as a novel prognostic marker in gastric cancer

Suppression of MAL gene expression is associated with colorectal cancer metastasis

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