Association and clinicopathologic significance of p38MAPK-ERK-JNK-CDC25C with polyploid giant cancer cell formation
We previously showed that cobalt chloride (CoCl2) 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.
CoCl2 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 CoCl2 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).
Compared to the control cells, p38MAPK and JNK expression were higher and CDC25C expression was lower in CoCl2-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.
The p38MAPK-ERK-JNK signaling pathway was involved in cell cycle progression and the formation of PGCCs by regulation of CDC25C.
KeywordsPolyploid giant cancer cells Cell cycle regulation G2/M arrest CDC25C MAPK
Polyploid giant cancer cells
Cancer stem cells
Fetal bovine serum
American Type Culture Collection
Protease inhibitor cocktail
Cell division cycle 25
Mitogen-activated protein kinase
Mitogen-activated protein kinase 8
SZ designed the study and contributed to manuscript writing; KL and QZ conducted the experiments and drafted the manuscript. RL participated in the sample collection, statistical analysis and contributed to manuscript writing. DJ helped in the finished of the study. YL and MZ participated in design and coordination and helped to draft the manuscript. All authors have read and approved the final manuscript.
This work was supported in part by grants from the National Natural Science Foundation of China (81672426), and the foundation of committee on science and technology of Tianjin (17ZXMFSY00120 and 17YFZCSY00700).
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Conflict of interest
The authors declare that they have no conflict of interest.
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