Downregulation of protein disulfide‑isomerase A3 expression inhibits cell proliferation and induces apoptosis through STAT3 signaling in hepatocellular carcinoma

Abstract

Protein disulfide-isomerase A3 (PDIA3) is a chaperone protein that modulates folding of newly synthesized glycoproteins and responds to endoplasmic reticulum (ER) stress. Previous studies reported that increased expression of PDIA3 in hepatocellular carcinoma (HCC) is a marker for poor prognosis. However, the mechanism remains poorly understood. The aim of the present study, therefore, was to understand the role of PDIA3 in HCC development. First, immunohistochemical staining of tissues from 53 HCC cases revealed that HCC tissues with high PDIA3 expression exhibited a higher proliferation index and contained fewer apoptotic cells than those with low expression. In addition, the knockdown of PDIA3 significantly inhibited cell proliferation and induced apoptosis in HCC cell lines. These results suggest that PDIA3 regulates cell proliferation and apoptosis in HCC. An examination of whether PDIA3 knockdown induced apoptosis through ER stress revealed that PDIA3 knockdown did not increase ER stress marker, 78 kDa glucose-regulated protein, in HCC cell lines. Furthermore, the association between PDIA3 and the signal transducer and activator of transcription 3 (STAT3) signaling pathway were investigated in vitro and in vivo. Immunofluorescence staining and co-immunoprecipitation experiments revealed colocalization and binding, respectively, of PDIA3 and STAT3 in HCC cell lines. The knockdown of PDIA3 decreased the levels of phosphorylated STAT3 (P-STAT3; Tyr705) and downstream proteins of the STAT3 signaling pathway: The anti-apoptotic proteins (Bcl-2-like protein 1, induced myeloid leukemia cell differentiation protein Mcl-1, survivin and X-linked inhibitor of apoptosis protein). In addition, PDIA3 knockdown provided little inhibitory effect on cell proliferation in HCC cell lines treated with AG490, a tyrosine-protein kinase JAK/STAT3 signaling inhibitor. Finally, an association was demonstrated between PDIA3 and P-STAT3 expression following immunostaining of 35 HCC samples. Together, the present data suggest that PDIA3 promotes HCC progression through the STAT3 signaling pathway.

Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells

“…We confirmed the role of PDIA1 in regulating the cell cycle and apoptosis, which was translated into a noticeable anti-cancer effect in the colony formation assay but not a substantial anti-proliferation effect in the classical assays. Altogether, our results showed that, apart from the tumorigenic role of intracellular PDI in the ER [ 33 ], PDIA1 played a vital role in regulating the adhesion of cancer cells and their transendothelial migration. The latter effects could be attributed to the extracellular PDIA1 function of regulating integrin-mediated adhesion and subsequent transendothelial migration of breast cancer cells, but not to the PDIA1-dependent regulation of ICAM-1 expression or changes in cellular bioenergetics in breast cancer or endothelial cells.…”

Knockdown of interferon‑stimulated gene 15 affects the sensitivity of hepatocellular carcinoma cells to norcantharidin

“…In the present study, the mRNA and protein expression levels of ISG15 in HCC tissues were found to be significantly increased in HCC tissues. Furthermore, according to the previous studies (20–22), the clinicopathological significance of ISG15 levels in patients with HCC was further investigated in the current study. It was observed that ISG15 levels in HCC tissues were significantly correlated with tumor size, TNM stage and differentiation.…”

“…Patient characteristics are listed in Table I. The clinicopathological significance of ISG15 levels in patients with HCC was studied according to methods described in the previous studies (20–22). Following surgical resection, the tissue samples were immediately snap frozen in liquid nitrogen and stored at −80°C.…”

Inhibitor for protein disulfide‑isomerase family A member 3 enhances the antiproliferative effect of inhibitor for mechanistic target of rapamycin in liver cancer: An in vitro study on combination treatment with everolimus and 16F16

“…Liver cancer with high PDIA3 expression follows an unfavorable course and is characterized by high proliferation activity and a low frequency of cell death. The expression of PDIA3 and its association with prognosis has been reported for other carcinomas (21,22,(38)(39)(40)(41). Furthermore, knock-down of PDIA3 may enhance the effect of radiation therapy in laryngeal cancer (38) and breast cancer (42).…”

“…PDIA3 is involved in the assembly and stability of signaling molecules such as mTOR and STAT3 (19,22). It has been shown that PDIA3 forms a complex with mTORC1 and stabilizes the signaling pathway (23).…”