Targeting HCCR expression resensitizes gastric cancer cells to chemotherapy via down-regulating the activation of STAT3

Abstract

The human cervical cancer oncogene (HCCR) has been found to be overexpressed in a variety of human cancers. However, the level of expression of HCCR and its biological function in gastric cancer are largely unknown. In this study, we evaluated HCCR expression in several gastric cancer cell lines and in one normal gastric mucosal cell line. We established a 5-FU-resistant gastric cancer cell subline, and we evaluated its HCCR expression. HCCR expression levels were high in gastric cancer lines, and expression was significantly increased in the 5-FU-resistant cancer cell subline. HCCR expression affected cell growth by regulating apoptosis in the cancer cells, and it had a positive correlation with p-STAT3 expression. Western blot and luciferase reporter assays showed that the activation of STAT3 upregulated HCCR expression in a positive feedback loop model. In vivo and in vitro studies showed that HCCR plays an important role in the apoptosis induced by 5-FU. Our data demonstrate that HCCR is probably involved in apoptosis and cancer growth and that it functions as a p-STAT3 stimulator in a positive feedback loop model. In gastric cancer cells, HCCR confers a more aggressive phenotype and resistance to 5-FU-based chemotherapy.

miR520c blocks EMT progression of human breast cancer cells by repressing STAT3

“…In gastric cancer, suppressing the activation of STAT3 resensitized cells to chemotherapy (27). Inhibition of STAT3 has influence on cell cytotoxic and cytostatic effect, it also reinforces anticancer immunosurveillance to increase therapeutic efficacy and stem cell-like phenotype (28). In human Wilms tumor SK-NEP-1 cells, inhibiting STAT3 and CDDP reduced cell growth in vivo (29).…”

LETMD1 Regulates Phagocytosis and Inflammatory Responses to Lipopolysaccharide via Reactive Oxygen Species Generation and NF-κB Activation in Macrophages

“…2 showed a stronger efficiency than others. However, complete suppression of LETMD1 expression caused inhibition of proliferation as described previously in various cancer cells (5,7,8). Therefore, we chose cells with shRNA no.…”

“…In contrast, silencing of LETMD1 results in a decrease in cell survival and proliferation via the promotion of p53, p21, and Bax expression (7). In addition, LETMD1 expression is positively associated with the phosphorylation of STAT3, which is associated with cellular proliferation and resistance to chemotherapy in gastric cancer (8). A previous report demonstrated that LETMD1 is localized at the mitochondrial outer membrane as a membrane-bound protein, and it has been implicated in resistance to UV and staurosporine-induced apoptosis, which might be caused by mitochondrial dysfunction (9).…”

Genome‐wide expression profiling and bioinformatics analysis of deregulated genes in human gastric cancer tissue after gastroscopy

“…For example, IL‐6 and IL‐11 are important regulatory factors in the process of inflammation leading to cancer development, and they may promote tumor aggressiveness correlating with patients’ survival time . STAT3 and NF‐κB activation, which causes gastric cancer progression and leads to enhanced cellular proliferation, is also correlated with poor survival . Currently, STAT3 inhibitors are emerging as a promising drug for gastric cancer .…”