Leptin's mitogenic effect in human liver cancer cells requires induction of both methionine adenosyltransferase 2A and 2β

Ramani, Komal; Yang, Heping; Xia, Meng; Iglesias–Ara, Ainhoa; Mato, José M.; Lu, Shelly C.

doi:10.1002/hep.22064

Cited by 75 publications

(134 citation statements)

References 32 publications

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“…Due to its mitogen effect, a condition of hyperleptinemia could favour the development of malignancies. In close agreement with this hypothesis, several lines of evidence support the role of leptin in the neoplastic processes [6][7][8][9]. Moreover, this is further supported by some genetic evidences showing a correlation between serum leptin levels, leptin receptor polymorphisms, and the risk of breast cancer [10,11].…”

supporting

confidence: 55%

Link between insulin and metabolic disorders in cancer: does leptin play a key role?

Malandrino¹,

Leggio²,

Addolorato³

et al. 2008

Breast Cancer Res Treat

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supporting

confidence: 55%

Link between insulin and metabolic disorders in cancer: does leptin play a key role?

Malandrino¹,

Leggio²,

Addolorato³

et al. 2008

Breast Cancer Res Treat

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“…We supposed that it might be related to cellular stress brought on by LV-shMAT2B, bcl-x L was able to induce apoptosis in response to cellular stress [30] . We found that LV-shMAT2B prevented proliferation in HepG2 cells, Leptin could induce proliferation in human hepatocarcinoma cells by up-regulating cyclin D1 [31] but Komal [30] found that Leptin could increase SAMe levels adipokine shown to be mitogenic in human liver cancer cell lines HepG2 and Huh7, and its mitogenic effect was also related with the expression of MAT2B.…”

Section: Discussionmentioning

confidence: 99%

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

Wang¹,

Liu²,

Liu³

et al. 2008

WJG

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AIM:To investigate the effects of lentivirus vector mediated short hairpin RNA interference targeting methionine adenosyltransferase 2β gene (LV-shMAT2B) on hepatocellular carcinoma (HCC) cells. METHODS:We constructed four plasmids of RNA interference targeting the MAT2B gene. After LVshMAT2B was transfected with L-02 cells and two kinds of HCC cells, cell viability and proliferation were measured with MTT and [3H]thymidine assays respectively. Flow cytometry was used to assess cell apoptosis. The level of S-adenosyl methionine (SAMe) in HepG2 cells was evaluated. The expressions of cyclin D1, cyclin D2, bcl-x L and bcl-x S were detected with western blot. RESULTS: We constructed LV-shMAT2B successfully. LV-shMAT2B was safe for human normal liver cells. LVshMAT2B caused dramatic reduction in proliferation c o m p a re d w i t h controls in HCC cel ls B el-7402 (P = 0.054) and HepG2 (P = 0.031). Flow cytometry analysis showed that cell apoptosis caused by LVshMAT2B was greater in HCC cells Bel-7402 and HepG2 than in control induced by scrambled siRNA (P = 0.047), but apoptosis rates in L-02 induced by LV-shMAT2B and scrambled siRNA respectively had no significant difference. Moreover, LV-shMAT2B significantly suppressed expression of MAT2B leading to growthinhibition effect on HCC cells by down-regulating cyclin D1. Apoptosis induced by LV-shMAT2B was involved in down-regulating bcl-x L and up-regulating bcl-x S . CONCLUSION: LV-shMAT2B can induce cell apoptosis and growth-inhibition in HCC cells. MAT2B may be a therapy target in HCC in the future.

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“…MAT2␤ expression is induced in cirrhosis and hepatocellular carcinoma (HCC). Importantly, increased MAT2A and MAT2␤ expression offer liver cancer cells a growth advantage (2,3).…”

Section: Methionine Adenosyltransferase (Mat)mentioning

confidence: 99%

Novel Function and Intracellular Localization of Methionine Adenosyltransferase 2β Splicing Variants

Xia

Chen

Wang

et al. 2010

Journal of Biological Chemistry

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Human methionine adenosyltransferase 2␤ (MAT2␤) encodes for two major splicing variants, V1 and V2, which are differentially expressed in normal tissues. Both variants are induced in human liver cancer and positively regulate growth. The aim of this work was to identify interacting proteins of V1 and V2. His-tagged V1 and V2 were overexpressed in Rosetta pLysS cells, purified, and used in a pulldown assay to identify interacting proteins from human colon cancer cell line RKO cell lysates. The eluted lysates were subjected to Western blot and in solution proteomic analyses. HuR, an mRNA-binding protein known to stabilize the mRNA of several cyclins, was identified to interact with V1 and V2. Immunoprecipitation and Western blotting confirmed their interaction in both liver and colon cancer cells. These variant proteins are located in both nucleus and cytoplasm in liver and colon cancer cells and, when overexpressed, increased the cytoplasmic HuR content. This led to increased expression of cyclin D1 and cyclin A, known targets of HuR. When endogenous expression of V1 or V2 is reduced by small interference RNA, cytoplasmic HuR content fell and the expression of these HuR target genes also decreased. Knockdown of cyclin D1 or cyclin A blunted, whereas knockdown of HuR largely prevented, the ability of V1 or V2 overexpression to induce growth. In conclusion, MAT2␤ variants reside mostly in the nucleus and regulate HuR subcellular content to affect cell proliferation. Methionine adenosyltransferase (MAT)2 is essential to life, because it is the only enzyme that catalyzes the formation of S-adenosylmethionine, the principal biological methyl donor (1). In mammals, two different genes, MAT1A and MAT2A, encode for two homologous MAT catalytic subunits, ␣1 and ␣2. MAT1A is expressed mostly in the liver while MAT2A is widely distributed. In adult liver, increased expression of MAT2A is associated with rapid growth or de-differentiation. Up until recently, the MAT2␤ gene was thought to encode for the regulatory subunit (␤) that is associated only with MAT2A-encoded enzyme (MATII) to lower its K m and K i for methionine and S-adenosylmethionine, respectively. MAT2␤ expression is induced in cirrhosis and hepatocellular carcinoma (HCC). Importantly, increased MAT2A and MAT2␤ expression offer liver cancer cells a growth advantage (2, 3).In a recent publication (4), we described novel functions of MAT2␤ that greatly increased its importance in biology. To study transcriptional regulation of MAT2␤, we cloned and characterized its 5Ј-flanking region and uncovered multiple alternate splicing variants and termed the two major variants V1 and V2. V1 encodes a 334-amino acid protein beginning MVGREKELSIHFVPGSCRLVE…. The alternatively spliced V2 utilizes a different first exon lying further upstream in the genomic sequence to encode a hypothetical 323-amino acid isoform beginning MPEMPEDMEQ… (4). The reading frame for both variants converge after this point and are identical. We examined their expression pattern in human tissues and H...

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Leptin's mitogenic effect in human liver cancer cells requires induction of both methionine adenosyltransferase 2A and 2β

Cited by 75 publications

References 32 publications

Link between insulin and metabolic disorders in cancer: does leptin play a key role?

Link between insulin and metabolic disorders in cancer: does leptin play a key role?

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

Novel Function and Intracellular Localization of Methionine Adenosyltransferase 2β Splicing Variants

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