Decreased expression of the type III TGF-β receptor enhances metastasis and invasion in hepatocellullar carcinoma progression

Abstract

Abstract. The transforming growth factor β (TGF-β) superfamily of cytokines is multifunctional and involved in the regulation of cell growth and differentiation. TGF-β can induce an epithelial-mesenchymal transition (EMT) of both epithelial and endothelial cells. This has consequences for cancer progression in regards to both migration and invasion abilities. The type III TGF-β receptor (TβRIII) is a ubiquitously expressed TGF-β co-receptor which regulates TGF-β signaling and the progression of various types of cancer. Previous studies have shown that TβRIII exhibits abnormal expression and plays an essential role in regulating cancer invasion and metastasis, while little is known in regards to its role in hepatocellular carcinoma (HCC) progression. In the present study, we designed the present research to study the role of TβRIII in the invasion and metastasis of HCC and the possible mechanisms involved. The results demonstrated decreased expression of TβRIII in HCC patient tissues and human HCC cell lines. TGF-β1 stimulation led to the increased migratory ability and reduced expression of TβRIII in HCC cells. In addition, knockdown of TβRIII by small interfering RNA (siRNA) promoted the migration and invasion of HCC cells and induced activation of the Smad2 and Akt pathways. All the results suggest that TβRIII is a novel suppressor of HCC progression.

Type III Transforming Growth Factor-β Receptor RNA Interference Enhances Transforming Growth Factor β3-Induced Chondrogenesis Signaling in Human Mesenchymal Stem Cells

“…We previously demonstrated that hMSCs expressed high levels of T β RIII and that TGF- β 3 reduced the expression of T β RIII at mRNA and protein levels [ 15 ]. Other studies demonstrated the specific role of TGF- β 1 in decreasing T β RIII mRNA and protein levels in cancer cells [ 20 , 21 ]. These findings were similar to those of our own study.…”

“…Hempel et al [ 21 ] showed the TGF- β 1-mediated downregulation of T β RIII mRNA expression by exerting effects on the ALK5/Smad2/3 pathway of the TGF β R3 gene proximal promoter. Three highly homologous isoforms of TGF- β in humans (TGF- β 1, TGF- β 2, and TGF- β 3) share a similar receptor complex and signaling pathway [ 20 ]. Therefore, the mechanism underlying the suppression by TGF- β 3 on T β RIII may be the same as that involved in TGF- β 1-mediated downregulation of T β RIII.…”

Precision medicine for hepatocelluar carcinoma using molecular pattern diagnostics: results from a preclinical pilot study

“…In HCCs as in other cancers such as ovarian cancer, TGFBR3 may function as a cancer suppressor, 12 and in pancreatic cancer loss of TGFBR3 expression promoted cancer progression. 22 In a pancreatic cancer model of the EMT, TGFBR3 suppresses the associated increased motility and invasiveness.…”

“…It has been shown, for example, that the presence of a certain dysfunctional subset of tumor-infiltrating NK cells is associated with tumor progression and is an independent indicator of poor outcome in HCC patients. 12 …”

Identification of exosomal miR-455-5p and miR-1255a as therapeutic targets for breast cancer

“…Accumulating evidence has proved that SMAD4 is a key downstream effector of transforming growth factor-β (TGF-β) signaling pathway, which is known to reduce breast cancer cell invasion and tumor-induced angiogenesis [41,42]. Zhang et al reported that the expression of SMAD4 and TGF-β receptor can be decreased by TGF-β1 stimulation and promoted the migration and invasion of hepatocellular carcinoma cells [43]. Thus, SMAD4 may also be down-regulated in breast cells and tissues, which has been validated in studies of Stuelten et al [44] and Zhong et al [45].…”