Inhibition of CYFIP2 promotes gastric cancer cell proliferation and chemoresistance to 5-fluorouracil through activation of the Akt signaling pathway

Abstract

Gastric cancer is a common gastrointestinal malignancy that accounts for a notable proportion of cancer-associated mortalities worldwide. Cytoplasmic fragile X mental retardation 1-interacting protein 2 (CYFIP2) is a novel p53-mediated pro-apoptotic protein whose expression is decreased in gastric cancer. However, whether decreased expression of CYFIP2 contributes to gastric carcinogenesis remains unclear. In order to mimic in vivo gastric tumor CYFIP2 expression levels, the present study used short hairpin RNA targeting CYFIP2 mRNA to silence CYFIP2 expression in MGC803 and SGC7901 gastric cancer cells. Gastric cancer cells with constitutively decreased CYFIP2 expression levels were successfully established. It was observed that CYFIP2 knockdown promoted proliferation and colony formation, and inhibited apoptosis in these cells. Furthermore, 5-fluorouracil (5-FU)-induced apoptosis was decreased following inhibition of CYFIP2 expression. In SGC7901 cells, protein expression of active caspase-3 and cleaved poly (ADP-ribose) polymerase was increased following treatment with 5-FU, while phosphorylated Akt serine/threonine kinase 1 (Akt) levels were decreased. These 5-FU-induced effects were reduced following CYFIP2 knockdown. In addition, inhibition of the Akt signaling pathway using the Akt inhibitor LY294002 restored CYFIP2-knockdown SGC7901 cell chemosensitivity to 5-FU. The results of the present study demonstrate that decreased CYFIP2 expression is associated with increased gastric tumor growth in vitro and that CYFIP2 knockdown-induced activation of the Akt pro-survival signaling pathway confers resistance to 5-FU-based chemotherapy in gastric cancer cells. Therefore, combined treatment with an Akt inhibitor and chemotherapeutic drugs may improve the efficacy of gastric cancer therapy in patients with low CYFIP2 expression.

Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma

“… 69 The protein product of CYFIP2 is involved in p53-dependent apoptosis induction. 70 Decreased expression of CYFIP2 can promote cancer cell growth in vitro 71 and has been reported in gastric cancer. 72 The roles of UBXN10 and NECAB2 in ESCC progression remain to be elucidated.…”

NUAK2 silencing inhibits the proliferation, migration and epithelial‑to‑mesenchymal transition of cervical cancer cells via upregulating CYFIP2

“…Furthermore, CYFIP2 has been suggested as a potential target in the treatment of Alzheimer's disease (23). In a previous study, CYFIP2 expression was reduced in gastric cancer, and inhibition of CYFIP2 promoted gastric cancer cell proliferation and chemotherapy resistance to 5-fluorouracil (11). A whole-exome sequencing study previously revealed that mutational dynamics and genetic variation, as well as aberrant DNA repair, tumor cell cycle control and apoptotic pathways were associated with CYFIP2 in endometrial cancer in the Taiwanese population (24).…”

“…The cytoplasmic FMR1-interacting protein (CYFIP) gene family has two highly conserved members, CYFIP1 and CYFIP2, which are ~145-kDa proteins with high homology (88% identity and 95% similarity) in their amino acid sequences ( 10 ). It has been reported that CYFIP2 mRNA expression is significantly reduced in gastric cancer tissues compared with that in non-cancerous tissues, and knockdown of CYFIP2 has been shown to promote cell proliferation and colony formation, and inhibit apoptosis ( 11 ). Additionally, overexpression of CYFIP2 has been demonstrated to promote apoptosis-like death of colorectal cancer cells ( 12 ).…”

The Downregulation of Prognosis- and Immune Infiltration-Related Gene CYFIP2 Serves as a Novel Target in ccRCC

“…Inhibition of CYFIP2 promoted cell proliferation and chemoresistance by activation of the Akt signal in gastric cancer. 23 CYFIP2 could act as a p53-inducible gene and promoted cell apoptosis in colorectal adenocarcinoma. 24 Activation cell death programs could suppress cell proliferation of tumor cells.…”