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Distinct functions of transforming growth factor-? signaling in c-MYC driven hepatocellular carcinoma initiation and progression.

ABSTRACT: Dysregulation of transforming growth factor-beta (TGF?) signaling has been implicated in liver carcinogenesis with both tumor promoting and inhibiting activities. Activation of the c-MYC protooncogene is another critical genetic event in hepatocellular carcinoma (HCC). However, the precise functional crosstalk between c-MYC and TGF? signaling pathways remains unclear. In the present investigation, we investigated the expression of TGF? signaling in c-MYC amplified human HCC samples as well as the mechanisms whereby TGF? modulates c-Myc driven hepatocarcinogenesis during initiation and progression. We found that several TGF? target genes are overexpressed in human HCCs with c-MYC amplification. In vivo, activation of TGF?1 impaired c-Myc murine HCC initiation, whereas inhibition of TGF? pathway accelerated this process. In contrast, overexpression of TGF?1 enhanced c-Myc HCC progression by promoting tumor cell metastasis. Mechanistically, activation of TGF? promoted tumor microenvironment reprogramming rather than inducing epithelial-to-mesenchymal transition during HCC progression. Moreover, we identified PMEPA1 as a potential TGF?1 target. Altogether, our data underline the divergent roles of TGF? signaling during c-MYC induced HCC initiation and progression.

SUBMITTER: Wang H

PROVIDER: S-EPMC7895828 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression.

Wang Haichuan H Wang Pan P Xu Meng M Song Xinhua X Wu Hong H Evert Matthias M Calvisi Diego F DF Zeng Yong Y Chen Xin X

Cell death & disease 20210219 2

Dysregulation of transforming growth factor-beta (TGFβ) signaling has been implicated in liver carcinogenesis with both tumor promoting and inhibiting activities. Activation of the c-MYC protooncogene is another critical genetic event in hepatocellular carcinoma (HCC). However, the precise functional crosstalk between c-MYC and TGFβ signaling pathways remains unclear. In the present investigation, we investigated the expression of TGFβ signaling in c-MYC amplified human HCC samples as well as th ...[more]

PMID: 33608500

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Project description:BACKGROUND: Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor beta (TGF-beta) expression and thick stromal fibrosis. However, the association of TGF-beta signaling with diffuse-type gastric carcinoma has not been investigated in detail. METHODS: We used a lentiviral infection system to express a dominant-negative TGF-beta type II receptor (dnTbetaRII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided. RESULTS: Expression of dnTbetaRII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnTbetaRII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnTbetaRII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnTbetaRII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1-knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P < .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues. CONCLUSIONS: Disruption of TGF-beta signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1.

Dataset Information

Distinct functions of transforming growth factor-? signaling in c-MYC driven hepatocellular carcinoma initiation and progression.

Publications

Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression.

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