Association and clinicopathologic significance of p38MAPK-ERK-JNK-CDC25C with polyploid giant cancer cell formation

Background We previously showed that cobalt chloride (CoCl 2 ) induction of polyploid giant cancer cells (PGCCs) was characterized by abnormal cell cycle-related protein expression and G2/M arrest. The role of the p38MAPK-ERK-JNK signaling pathway in cell cycle regulation has been reported, but the mechanism by which p38MAPK-ERK-JNK regulates PGCCs formation remains unclear. This study examined p38MAPK-ERK-JNK-CDC25C expression in PGCCs and their daughter and control cells and assessed the clinicopathological significance of p38MAPK, ERK, JNK, and CDC25C expression in human ovarian and breast cancers. Methods CoCl 2 was used to induce the formation of PGCCs in HEY and BT-549 cells. Western blotting and immunocytochemical staining were used to compare the expression and subcellular localization of p38MAPK, ERK, JNK, and CDC25C in the control group and CDC25C knockdown before and after CoCl 2 treatment. The specific combination of p38MAPK and ERK with pCDC25C-Ser216 was detected by immunoprecipitation. In addition, p38MAPK, ERK, JNK, and CDC25C immunohistochemical staining were performed to compare the clinicopathologic significances in 81 cases of ovarian cancer tissue, including 20 cases of primary breast cancer with lymph node metastasis (group I), and their corresponding metastatic lymph nodes (group II), 31 cases of primary breast cancer without metastasis (group III), and 10 cases of benign breast tumors (group IV). Breast tumor tissue from 229 was divided into two groups: 167 cases of primary invasive breast cancer (group 1) and 62 cases of lymph node metastatic breast cancer (group 2). Results Compared to the control cells, p38MAPK and JNK expression were higher and CDC25C expression was lower in CoCl 2 -treated cells. Moreover, ERK displayed a trend of increased expression in HEY PGCCs and decreased expression in BT-549 PGCCs. p38MAPK and ERK regulated CDC25C by phosphorylating the CDC25C-Ser216 site and participated in the G2/M phase transition. Immunohistochemical (IHC) analysis of the ovarian tumor tissues showed significant positive staining rates of p38MAPK ( P = 0.001), ERK ( P = 0.002), JNK ( P = 0.000), and CDC25C ( P = 0.000) among the four groups. In breast tumor tissues, the overall expression in p38MAPK ( P = 0.029), ERK ( P = 0.002), JNK ( P = 0.013), and CDC25C ( P = 0.001) also differed significantly between the two groups. Conclusion The p38MAPK-ERK-JNK signaling pathway was involved in cell cycle progression and the formation of PGCCs by regulation of CDC25C.