Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

Abstract

Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-b (TGF-b) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-b signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-b signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-b receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-b. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (Po0.001), poor differentiation (Po0.001), portal vein invasion (P ¼ 0.002), intrahepatic metastasis (IM) (Po0.001), and shorter recurrence-free survival (P ¼ 0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC. Hepatocellular carcinoma (HCC) is a common cause of death from cancer worldwide. 1 Prolonged infection with hepatitis virus often causes chronic hepatitis, followed by liver cirrhosis. 2 During the development of these liver diseases, transforming growth factor-b (TGF-b) has an important role in fibrosis of the lesions. 3 HCCs mainly occur in those injured livers with activated TGF-b signaling, although TGF-b inhibits hepatocyte cell growth in the normal liver. 4,5 TGF-b signaling is activated when a TGF-b ligand binds to its receptor on the cell membrane. The downstream effectors, SMAD2 and SMAD3, together with SMAD4, translocate to the nucleus and regulate the expression of various genes, including cyclin-dependent kinase inhibitor 1A (CDKN1A), which is involved in cell growth arrest. 6,7 TGF-b signaling is also suggested to be involved in the malignant progression of tumors. TGF-b can induce epithelial-mesenchymal transition and promote tumor cell invasion, and may also have angiogenic and immunosuppressive effects on the tumor microenvironment, all of which promote metastasis. 8 Mutations in the TGF-b superfamily genes have been found in various cancers. The TGF-b receptor II (TGFBR2) gene is frequently mutated in colon cancers, 9,10 gastric cancers, 10,11 and in gliomas 12 with microsatellite instability. SMAD4 mutations occur mainly in pancreatic cancers, in which the SMAD4 gene was first identified as a tumorsuppressor gene. 13 In HCCs, however, mutations in TGF-b superfamily genes are rare, 14,15 and alteration of TGF-b signaling is still unclear and controversial. To investigate alterations of TGF-b signaling in HCC progression, we compared the expression profiles of TGF-b signalingrelated genes in HCC cells exhibiting different metastatic potential. We...

Molecular Pathogenesis of Hepatocellular Carcinoma: Altering Transforming Growth Factor-β Signaling in Hepatocarcinogenesis

“…Recently we reported that reduced TGFBR2 expression in HCC correlated with intrahepatic metastasis [13]. Approximately 25% of HCCs showed decreased staining for TGFBR2 compared with adjacent non-cancerous hepatocytes (fig.…”

“…Indeed, the role of TGF-β signaling in HCC is controversial. Recently, we showed that reduced TGF-β receptor type II (TGFBR2) expression in HCC correlated with intrahepatic metastasis and shorter time to recurrence [13]. Various roles of TGF-β signaling may be implicated in multistep hepatocarcinogenesis.…”

“…TGF-β overexpression is frequently found in HCCs as well as other cancers. Treatment with TGF-β results in the growth arrest of HCC cells expressing TGFBR2 [13], indicating that TGF-β signaling has a tumor-suppressive role in HCC cells as well as normal hepatocytes. Mechanisms to escape TGF-β-induced growth arrest may be necessary for HCC progression.…”

MicroRNA-302d downregulates TGFBR2 expression and promotes hepatocellular carcinoma growth and invasion

“…Reduced expression or loss of the TGFβ type I and type II receptors (TGFBR1 and TGFBR2) has been reported in various types of cancer, including HCC (23)(24)(25). TGFBR2 has been identified as the direct target of numerous miRNAs, including miR-655, miR-520c, miR-373 and miR-211 (26).…”

Immunotherapy for hepatocellular carcinoma

“…TGF-β1 is also a polypeptide cytokine abundant in the liver, with high biological activity. The expression of TGF-β1 are abnormally elevated in liver cancer (49), which mainly involves the inhibition of innate immune and stimulation of Tregs generation to destroy the anti-tumor immune response, resulting in progression of malignancies (50).…”