Abstract
BackgroundGrowth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others. However, the function of GDF15 in cervical cancer has not yet been reported.MethodsImmunohistochemistry was used to detect GDF15 expression in normal cervix and in different cervical cancer lesions. Cell growth curves, MTT, tumor formation assays and flow cytometry were utilized to observe the effects of ectopic GDF15 expression on the proliferation and cell cycle of cervical cancer cells. Real-time PCR, western blotting and immunoprecipitation assays were conducted to measure the expression of genes related to the cell cycle and the PI3K/AKT and MAPK/ERK signaling pathways. A chromatin immunoprecipitation assay was performed to confirm whether C-myc bound to a specific region of the GDF15 promoter. Inhibitor treatment and immunoprecipitation assays were employed to identify the association between GDF15 and ErbB2.ResultsGDF15 expression gradually increased during the progression of cervical carcinogenesis. GDF15 promoted cervical cancer cell proliferation via exogenous rhGDF15 treatment or the use of gene editing technology in vitro and in vivo and significantly accelerated the cell cycle transition from G0/G1 to S phase. The expression of p-ErbB2, p-AKT1, p-Erk1/2, CyclinD1 and CyclinE1 was up-regulated and the expression of p21 was down-regulated in GDF15-overexpressing and rhGDF15-treated cervical cancer cells. C-myc trans-activated GDF15 expression by binding to the E-box motifs in the promoter of GDF15 and contributed to the positive feedback of GDF15/C-myc/GDF15. Furthermore, GDF15 bound to ErbB2 in a protein complex in cervical cancer cells.ConclusionsOur data demonstrated that GDF15 promoted the proliferation of cervical cancer cells via the up-regulation of CyclinD1 and CyclinE1 and the down-regulation of p21 through both the PI3K/AKT and MAPK/ERK signaling pathways in a complex with ErbB2.
Highlights
Growth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others
In a follow up study performed with the TCGA database (TCGA_CESC_exp_HiSeqV2), women with high GDF15 expression showed a statistically significant higher risk of cancer development and shorter disease-free survival time within 10 years compared to women with low GDF15 expression
These results strongly suggested that GDF15 accelerated cell cycle progression in cervical cancer cells by targeting cdc25A, Cyclin-dependent kinase-2 (CDK2), Cyclin-dependent kinase-4 (CDK4), p21, CyclinD1 and CyclinE1 through alterations in the expression of FOXO1 and C-myc
Summary
Growth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others. Cervical cancer is the second most common cancer in women in developing countries after breast cancer, and recent findings indicate an increased risk for young women under 25 years of age who may be predisposed to develop cervical cancer [1] Multistep factors such as proto-oncogene activation, tumor suppressor gene inactivation, epigenetic alterations, and genomic instability are involved in the development of cervical cancer [2, 3]. Substantial evidence has indicated that various oncogenes (such as LGR5 and DAX1) and suppressor genes (such as KLF4 and SLUG) exhibit abnormal expression during the development and progression of cervical carcinoma [4,5,6,7], which suggests the important role of gene activity in the carcinogenesis of cervical cancer. This study aimed to fully explore the function and mechanisms of GDF15 in cervical carcinogenesis
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