Down-regulation of transforming growth factor β receptor type III in hepatocellular carcinoma is not directly associated with genetic alterations or loss of heterozygosity

Abstract

Abstract. The transforming growth factor receptor III (TGFßRIII) is the most abundant and essential TGF-ß binding protein that functions as a co-receptor with other receptors in TGF-ß signaling. In earlier studies, expression of TGFßRIII was reported to be decreased in a variety of human cancers. Functional assessment of TGFßRIII was performed in many previously studied cancers but not in hepatocellular carcinoma. Therefore, in this study, we investigated the expression and genetic alterations of TGFßRIII in hepatocellular carcinoma (HCC) by quantitative real-time PCR (qRT-PCR) and singlestrand conformation polymorphism (SSCP) analysis. The qRT-PCR showed down-regulation of TGFßRIII in the tumor samples. To investigate whether genetic alterations mediated decreased expression of TGFßRIII, we performed mutation analysis of 67 human HCC tissues by SSCP and direct sequencing. We found five previously reported and one novel single nucleotide polymorphisms in exons 2, 3, 5, 13 and 14, but no mutations were detected. These polymorphisms were not associated with amino acid changes except for a base change found in exon 2 (TCC→TTC, S15F). The loss of heterozygosity (LOH) analysis performed on 10 tumors and corresponding normal pairs, showed a low rate of LOH (2/10). The results of this study suggest that TGFßRIII is transcriptionally down-regulated in hepatocellular carcinoma. In addition, genetic alterations did not appear to be associated with the reduced expression level of TGFßRIII. To clarify the role of TGFßRIII in hepatocellular tumor development and progression, functional analysis is needed in future studies.

Betaglycan Gene (TGFBR3) Polymorphism Is Associated with Increased Risk of Endometrial Cancer

“…Altered betaglycan expression may be responsible for impaired TGFβ signaling initiated by TGFβ isoforms and simultaneous redirection of this signal to Smad-independent pathways. TGFBR3 gene downregulation has been stated in the case of different cancers, and the observed decline in the expression of the TGFBR3 gene appears to be correlated with cancer progression, when tumor cells demonstrate an increase invasiveness and metastatic potential [17][18][19][20][21][22][23][25][26][27][28].…”

“…Betaglycan gene (TGFBR3), located on chromosome 1, encodes a transmembrane proteoglycan. Literature data and our previous studies indicate the contribution of betaglycan loss to the development and progression of cancers originated from different tissue types, i.e., breast, endometrium, ovary, prostate, lung, bladder, liver, pancreas, kidney, and neuroblastoma [17][18][19][20][21][22][23][24][25][26][27][28]. Down-regulation of betaglycan expression seems to be engaged in the impaired TGFβ signaling initiated by the TGFβ2 isoform to which it displays the highest affinity.…”

“…Obtained results suggest that studied SNPs are involved in the observed betaglycan down-regulation in endometrial cancer; however, the only one of them, i.e., rs2296621 (c.2285 − 99G > T), seems to be related to pronounced tumor aggressiveness. Bioinformatic analysis using RegulomeDB showed that rs12566180 (c. According to the literature data, polymorphism of the TGFBR3 gene is considered as a mechanism responsible for betaglycan down-regulation of HBV-infection related hepatocellular carcinoma and ovarian cancer [17,[43][44][45]. Bae et al [17] evaluated six SNPs, i.e., rs1805110 (p.Ser15Phe), rs2810904 (p.Ala72=), rs2306888 (p.Ser173=), rs1805113 (p.Phe675=), rs284878 (p.Thr749=) and newly identified SNP p.Thr711=, in the TGFBR3 gene in a group consisting of 67 patients with hepatocellular carcinoma.…”

“…Bioinformatic analysis using RegulomeDB showed that rs12566180 (c. According to the literature data, polymorphism of the TGFBR3 gene is considered as a mechanism responsible for betaglycan down-regulation of HBV-infection related hepatocellular carcinoma and ovarian cancer [17,[43][44][45]. Bae et al [17] evaluated six SNPs, i.e., rs1805110 (p.Ser15Phe), rs2810904 (p.Ala72=), rs2306888 (p.Ser173=), rs1805113 (p.Phe675=), rs284878 (p.Thr749=) and newly identified SNP p.Thr711=, in the TGFBR3 gene in a group consisting of 67 patients with hepatocellular carcinoma. In their study, rs1805110 (p.Ser15Phe) polymorphism was found to be present at a high frequency, i.e., in about 98.5% of examined cancer samples; however, the lack of case-control comparison made it impossible to confirm the association between rs1805110 (p.Ser15Phe) SNP occurrence and betaglycan down-regulation [17].…”

“…Bae et al [17] evaluated six SNPs, i.e., rs1805110 (p.Ser15Phe), rs2810904 (p.Ala72=), rs2306888 (p.Ser173=), rs1805113 (p.Phe675=), rs284878 (p.Thr749=) and newly identified SNP p.Thr711=, in the TGFBR3 gene in a group consisting of 67 patients with hepatocellular carcinoma. In their study, rs1805110 (p.Ser15Phe) polymorphism was found to be present at a high frequency, i.e., in about 98.5% of examined cancer samples; however, the lack of case-control comparison made it impossible to confirm the association between rs1805110 (p.Ser15Phe) SNP occurrence and betaglycan down-regulation [17]. Similar results were presented by Xin et al [45].…”