Sigma-1 receptor (σ1R) is downregulated in hepatic malignant tumors and regulates HepG2 cell proliferation, migration and apoptosis

Abstract

Sigma-1 receptor (σ1R), an important transmembrane structural protein, has been demonstrated to be overexpressed in various types of human cancer, and has been confirmed to be involved in many biological behaviors during tumorigenesis and tumor progression. The aim of the present study was to explore the essential role of σ1R in hepatic malignant tumors (HMTs), which, to the best of our knowledge, has not been reported to date. We assessed σ1R expression in hepatocellular carcinoma (HCC) tissues and found that σ1R was significantly decreased in HCC when compared with that in benign liver tissues (P<0.01). Additionally, the expression of σ1R was shown to be inversely correlated with HCC grade (r=-0.424, P=0.021, Kendall's τ-b-test). We further used a FLAG‑SV40‑neomycin‑plasmid strategy to increase σ1R expression in the HepG2 hepatoblastoma cell line. Overexpression of σ1R impaired cell proliferation, inhibited cell migration, induced cell cycle arrest at G1 phase, and increased cell apoptosis in vitro. Furthermore, overexpression of σ1R decreased the expression levels of STAT-3 and NF-κB, which provided insight into the underlying mechanisms of σ1R-associated HMT development and progression. These findings suggest that the decreased expression of σ1R plays an essential role in hepatic tumorigenesis, and that it may serve as a potential predictive factor and therapeutic target for the treatment of HMTs.

Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α

“…In a study carried out on liver tissue from 30 patients (26 men and 4 women) with hepatocellular carcinoma (HCC), a decrease in the expression of SigR1 was observed compared to the non-tumoral liver [15]. This result contrasts with what we observed in HCA.…”

“…In the manuscript by Xu and colleagues, beyond the fact that HNF1α status was likely wild-type (as in most HCC), 29 HCC were analyzed, including 26 from men while our study focused on 349 HCA, 85% of which developed in women. Furthermore, the etiology of HCC was not well defined but could be linked to cirrhosis [15], which is not an underlying condition state in HCA. Finally, the opposite effect of overexpression of SigR1 on the proliferation of HepG2 cells could be because the cells may originate from different sources and exhibit different characteristics [31].…”

“…Likewise, it has been reported that the level of expression of SigR1 was related to the aggressiveness of cancer: the more SigR1 is expressed, the more aggressive the tumor is [ 11 , 14 ]. In contrast, Simony-Lafontaine et al established that in human breast tumors, the level of SigR1 was correlated to patient survival, suggesting that SigR1 inhibits tumor growth [ 12 ] and more recently, a decrease in the expression of SigR1 in Hepatocellular carcinoma [ 15 ] has been shown. Nevertheless, many studies show the involvement of SigR1 in cancer [ 16 , 17 ], and, for example, SigR1 has been suggested as a potential prognosis and diagnostic marker for breast tumors [ 12 ] and prostate cancers [ 18 ].…”

Human hepatocellular carcinoma: Protection by melatonin

“…PDTC is known as the specific NF-κB inhibitor. NF-κB is involved in proliferation, apoptosis resistance, migration, invasion, angiogenesis and immunosuppression (Dong et al, 2018;Liang, Huang, Chang, & Hou, 2018;Luo et al, 2018;Mok et al, 2018;Ordonez et al, 2014;Xu et al, 2018;Zhang et al, 2018) phosphorylated IkBα NF-κB Phosphorylated IKK NF-κB Chloroquine Chloroquine is an autophagy inhibitor. Chloroquine promotes apoptosis and impairs DNA repair in cancer cells (Dash et al, 2016;Ordoñez et al, 2015) Baf-A1 Baf-A1 is an autophagy inhibitor.…”

Calcium transfer between endoplasmic reticulum and mitochondria in liver diseases

“…In contrast, S1R expression decreased in liver tissues of HCC when compared with that in benign ones and was negatively correlated with HCC grade. Moreover, overexpression of S1R impaired cell proliferation, inhibited cell migration, induced cell cycle arrest at the G1 phase, and increased cell apoptosis in vitro [66]. Consistently, Bai et al found that erastin and sorafenib could significantly induce S1R protein expression, which might be a promising new therapeutic strategy [67].…”