Abstract
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 the mechanisms whereby TGFβ modulates c-Myc driven hepatocarcinogenesis during initiation and progression. We found that several TGFβ target genes are overexpressed in human HCCs with c-MYC amplification. In vivo, activation of TGFβ1 impaired c-Myc murine HCC initiation, whereas inhibition of TGFβ pathway accelerated this process. In contrast, overexpression of TGFβ1 enhanced c-Myc HCC progression by promoting tumor cell metastasis. Mechanistically, activation of TGFβ promoted tumor microenvironment reprogramming rather than inducing epithelial-to-mesenchymal transition during HCC progression. Moreover, we identified PMEPA1 as a potential TGFβ1 target. Altogether, our data underline the divergent roles of TGFβ signaling during c-MYC induced HCC initiation and progression.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancerrelated deaths worldwide[1]
To investigate the genes and pathways regulated by cMYC amplification, we performed bioinformatics analysis of HCC samples from The Cancer Genome Atlas (TCGA) LIHC cohort and identified 2198 genes whose expression levels were deregulated in HCCs harboring c-MYC amplification (Supplementary Table 3)
The expression of TGFβ target genes, such as E2F523, RHOA24, RBX125, and PPP2R1A26, was higher in HCC samples with c-MYC amplification (MYC Amp) than those without amplification (MYC Wt) (Fig. 1b). To further substantiate this observation, we investigated whether TGFβ signaling is activated in mouse HCC induced by hydrodynamic tail vein injection (HTVi) of the c-Myc protooncogene[14]
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancerrelated deaths worldwide[1]. Etiologic factors including chronic hepatitis B and C virus infection, aflatoxin exposure, and heavy alcohol consumption contribute to cycles of hepatocyte damage/cell death and compensatory regeneration[3]. These events, together with the progressive accumulation of genetic and epigenetic changes induces a “field defect”. The pathophysiology of HCC might be thoroughly divergent during the initiation and progression stages[5]. There is a need to better delineate the distinct molecular pathways regulating HCC initiation and progression to develop innovative and effective diagnostic and therapeutic approaches
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