Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocellular carcinoma

Wang, Qun; Liu, Quanyan; Liu, Zhisu; Qian, Qun; Sun, Qiang; Pan, Dingyu

doi:10.3748/wjg.14.4633

Cited by 9 publications

(11 citation statements)

References 30 publications

(32 reference statements)

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“…In addition, the transfection of miR-21-3p mimics increased intracellular SAM contents. Conflicting results have been reported on intracellular SAM contents increasing or decreasing after the knockdown of MAT2A in hepatoma cells [16]–[18], whereas, intracellular SAM contents were increased in all relevant studies after knockdown of MAT2B or both MAT2A and MAT2B [17]–[19]. Consistent with previous studies, our results showed that miR-21-3p directly reduced the expression of both MAT2A and MAT2B resulting in increasing intracellular SAM contents that have been proven to impair the growth of hepatoma cells.…”

Section: Discussionsupporting

confidence: 85%

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MicroRNA-21-3p, a Berberine-Induced miRNA, Directly Down-Regulates Human Methionine Adenosyltransferases 2A and 2B and Inhibits Hepatoma Cell Growth

2013

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Methionine adenosyltransferase (MAT) is the cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM), the principal biological methyl donor and a key regulator of hepatocyte proliferation, death and differentiation. Two genes, MAT1A and MAT2A, encode 2 distinct catalytic MAT isoforms. A third gene, MAT2B, encodes a MAT2A regulatory subunit. In hepatocellular carcinoma (HCC), MAT1A downregulation and MAT2A upregulation occur, known as the MAT1A:MAT2A switch. The switch is accompanied with an increasing expression of MAT2B, which results in decreased SAM levels and facilitates cancer cell growth. Berberine, an isoquinoline alkaloid isolated from many medicinal herbs such as Coptis chinensis, has a wide range of pharmacological effects including anti-cancer effects. Because drug-induced microRNAs have recently emerged as key regulators in guiding their pharmacological effects, we examined whether microRNA expression is differentially altered by berberine treatment in HCC. In this study, we used microRNA microarrays to find that the expression level of miR-21-3p (previously named miR-21*) increased after berberine treatment in the HepG2 human hepatoma cell line. To predict the putative targets of miR-21-3p, we integrated the gene expression profiles of HepG2 cells after berberine treatment by comparing with a gene list generated from sequence-based microRNA target prediction software. We then confirmed these predictions through transfection of microRNA mimics and a 3′ UTR reporter assay. Our findings provide the first evidence that miR-21-3p directly reduces the expression of MAT2A and MAT2B by targeting their 3′ UTRs. In addition, an overexpression of miR-21-3p increased intracellular SAM contents, which have been proven to be a growth disadvantage for hepatoma cells. The overexpression of miR-21-3p suppresses growth and induces apoptosis in HepG2 cells. Overall, our results demonstrate that miR-21-3p functions as a tumor suppressor by directly targeting both MAT2A and MAT2B, indicating its therapeutic potential in HCC.

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Section: Discussionsupporting

confidence: 85%

“…Because MAT2A and MAT2B play crucial role in facilitating the growth of hepatoma cells, they are valid targets for antineoplastic therapy. Recent studies have shown that silencing MAT2A and MAT2B by using small interfering RNA substantially suppress growth and induce apoptosis in hepatoma cells [16]–[19].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-21-3p, a Berberine-Induced miRNA, Directly Down-Regulates Human Methionine Adenosyltransferases 2A and 2B and Inhibits Hepatoma Cell Growth

2013

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“…inhibition by downregulating cyclin D1. Moreover, apoptosis of HCC cells induced by LV-shRnA of MAT2B was involved in downregulating BCL-XL and upregulating BCL-XS (6). In both liver and colon cancers, MAT2B interacted with gIT1 and formed a scaffold to regulate Ras/Raf/MeK1/2 activity and therefore promoted cell growth and tumorigenesis (7,8).…”

Section: Lentivirus-mediated Downregulation Of Mat2b Inhibits Cell Prmentioning

confidence: 99%

“…Although MAT2B is known as a gene encoding regulatory subunit for changing MATII enzymatic activity, recent studies have reported that MAT2B also has several kinds of specific biologic fuctions, especially in cancer. MAT2B expression is elevated in human hepatocellular carcinoma and colon cancer which promotes the growth advantage or cell cycle of tumor cells (5)(6)(7)(8)(9). In HCC cells, MAT2B knockdown led to growth…”

Section: Introductionmentioning

confidence: 99%

Lentivirus-mediated downregulation of MAT2B inhibits cell proliferation and induces apoptosis in melanoma

Lei

Zhang

et al. 2016

International Journal of Oncology

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Malignant melanoma is the most lethal of skin cancers and its pathogenesis is complex and heterogeneous. The efficacy of conventional therapeutic regimens for melanoma remains limited. Thus, it is important to explore novel effective therapeutic targets in the treatment of melanoma. The MAT2B gene encodes for the regulatory subunit of methionine adenosyltransferase (MAT). Recent studies have suggested that MAT2B may have functional roles other than modulating catalytic activity of MAT. In order to identify the roles of MAT2B in the tumorigenesis of malignant melanoma, we compared MAT2B expression profile in melanoma tissues with that in benign nevus samples. We employed lentivirusmediated RNAi to downregulate the expression of MAT2B in malignant melanoma cell lines (A375 and Mel-RM), and investigated the effects of MAT2B on cell growth, colonyformation ability and apoptosis in vitro, as well as tumor growth of a xenograft model in vivo. The expression levels of BCL2 and XAF1 proteins, which were closely related to tumor cell apoptosis, were analyzed by western blot analysis. Our data showed that MAT2B was elevated in both primary and metastatic melanoma tissues compared with benign nevus samples. Lentivirus-mediated downregulation of MAT2B suppressed cell growth, colony formation and induced apoptosis in A375 and Mel-RM cell lines in vitro, affected protein expression of BCL2 and XAF1, extended the transplanted tumor growth in vivo. These results indicated that MAT2B was critical in the proliferation of melanoma cells and tumorigenicity. It may be considered as a potential anti-melanoma therapeutic target.

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“…In HCC, MAT gene expression is switched from MAT1A to MAT2A , accompanied by an induction of MAT2A and MAT2B protein levels [5,13,14]. This switch in MAT gene expression is proposed to facilitate the rapid cell growth and provide a proliferative advantage for cancer [15], and also makes MAT2A/MAT2B an attractive target for chemoprevention and treatment of HCC [16]. …”

Section: Introductionmentioning

confidence: 99%

Insight into S-adenosylmethionine biosynthesis from the crystal structures of the human methionine adenosyltransferase catalytic and regulatory subunits

Shafqat

Muniz

Pilka

et al. 2013

Biochemical Journal

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MAT (methionine adenosyltransferase) utilizes L-methionine and ATP to form SAM (S-adenosylmethionine), the principal methyl donor in biological methylation. Mammals encode a liver-specific isoenzyme, MAT1A, that is genetically linked with an inborn metabolic disorder of hypermethioninaemia, as well as a ubiquitously expressed isoenzyme, MAT2A, whose enzymatic activity is regulated by an associated subunit MAT2B. To understand the molecular mechanism of MAT functions and interactions, we have crystallized the ligand-bound complexes of human MAT1A, MAT2A and MAT2B. The structures of MAT1A and MAT2A in binary complexes with their product SAM allow for a comparison with the Escherichia coli and rat structures. This facilitates the understanding of the different substrate or product conformations, mediated by the neighbouring gating loop, which can be accommodated by the compact active site during catalysis. The structure of MAT2B reveals an SDR (short-chain dehydrogenase/reductase) core with specificity for the NADP/H cofactor, and harbours the SDR catalytic triad (YxxxKS). Extended from the MAT2B core is a second domain with homology with an SDR sub-family that binds nucleotide-sugar substrates, although the equivalent region in MAT2B presents a more open and extended surface which may endow a different ligand/protein-binding capability. Together, the results of the present study provide a framework to assign structural features to the functional and catalytic properties of the human MAT proteins, and facilitate future studies to probe new catalytic and binding functions.

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Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocellular carcinoma

Cited by 9 publications

References 30 publications

MicroRNA-21-3p, a Berberine-Induced miRNA, Directly Down-Regulates Human Methionine Adenosyltransferases 2A and 2B and Inhibits Hepatoma Cell Growth

MicroRNA-21-3p, a Berberine-Induced miRNA, Directly Down-Regulates Human Methionine Adenosyltransferases 2A and 2B and Inhibits Hepatoma Cell Growth

Lentivirus-mediated downregulation of MAT2B inhibits cell proliferation and induces apoptosis in melanoma

Insight into S-adenosylmethionine biosynthesis from the crystal structures of the human methionine adenosyltransferase catalytic and regulatory subunits

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