Chen‐Chen Ren

A Slug‐dependent mechanism is responsible for tumor suppression of p53‐stabilizing compound CP‐31398 in p53‐mutated endometrial carcinoma

AbstractMutation in the tumor suppressor gene p53 is the most frequent molecular defect in endometrial carcinoma (EC). Recently, CP‐31398, a p53‐stabilizing compound, has been indicated to possess the ability to alter the expression of non‐p53 target genes in addition to p53 downstream genes in tumor cells. Herein, we explore the alternative mechanisms underlying the restoration of EC tumor suppressor function in mutant p53 by CP‐31398. A p53‐mutated EC cell was constructed in AN3CA cells with restored or partial loss of Slug using lentiviral vectors, followed by treatment with 25 μM CP‐31398. A p53‐independent mechanism of CP‐31398 was confirmed by the interaction between mouse double minute 2 homolog (MDM2) and Slug AN3CA cells treated with IWR‐1 (inhibitor of Wnt response 1). Furthermore, the AN3CA cells were treated with short hairpin RNA against Slug, Wnt‐specific activators (LiCl) or inhibitors (XAV‐939) followed by CP‐31398 treatment. Moreover, AN3CA cell proliferation and apoptosis were examined. A tumorigenicity assay was conducted in nude mice. CP‐31398 could promote the apoptosis of p53‐mutated EC cells, while Slug reversed this effect. Slug ubiquitination was found to occur via binding of Slug to MDM2 in AN3CA cells. We found that CP‐31398 increased the GSK‐3ß, p‐Slug, Puma, Wtp53, and Bax expressions whereas Wnt, Mtp‐53, Slug, Bcl‐2, and Ki‐67 expressions were decreased. However, these findings were reversed following the activation of the Wnt pathway and overexpression of Slug. Finally, the in vivo experimental evidence confirmed that CP‐31398 with depleted Slug suppressed tumor growth by downregulating the Slug. Collectively, CP‐31398‐regulated Slug downregulation represses the p53‐mutated EC via the p53/Wnt/Puma pathway.

Efficacy and safety of neoadjuvant chemotherapy versus primary debulking surgery in patients with ovarian cancer: a meta-analysis

Neoadjuvant chemotherapy (NACT) for the treatment of epithelial ovarian cancer (EOC) has remained controversial. This meta-analysis was performed to systematically assess the efficacy and safety of NACT versus primary debulking surgery (PDS) in patients with EOC. PubMed, Embase, ClinicalTrials.gov, and Cochrane Library were queried to assess the therapeutic value of NACT versus PDS in EOC. Electronic databases were queried by using the keywords "ovarian cancer/neoplasms", "primary debulking surgery", and "neoadjuvant chemotherapy". The available trials were pooled, and hazard ratios (HRs), relative risk ratios (RRs) and associated 95% confidence intervals (95% CIs) were determined. Sixteen trials involving 57,450 participants with EOC (NACT, 9,475; PDS, 47,975) were evaluated. We found that NACT resulted in markedly decreased overall survival than PDS in patients with EOC (HR=1.30; 95% CI=1.13-1.49; heterogeneity: p<0.001, I²=82.7%). Furthermore, our results demonstrated that the NACT group displayed increased completeness of debulking removal (RR=1.69, 95% CI=1.32-2.17; heterogeneity: p<0.001, I²=81.9%), and reduced risk of postsurgical death (RR=0.18, 95% CI=0.06-0.51; heterogeneity: p=0.698, I²=0%) and major infection (RR=0.29, 95% CI=0.17-0.51; heterogeneity: p=0.777, I²=0%) compared with patients administered PDS. This meta-analysis indicated that NACT results in increased completeness of debulking removal, and reduced risk of postsurgical death and major infection compared with PDS, while PDS is associated with improved survival in comparison with NACT in EOC patients. PROSPERO Identifier: CRD42019120625.

RPL34‐AS1–induced RPL34 inhibits cervical cancer cell tumorigenesis via the MDM2‐P53 pathway

AbstractRibosomal proteins (RPs) are important components of ribosomes and related to the occurrence and development of tumors. However, little is known about the effects of the RP network on cervical cancer (CC). In this study, we screened differentially expressed RPL34 in CC by high‐throughput quantitative proteome assay. We found that RPL34 acted as a tumor suppressor and was downregulated in CC and inhibited the proliferation, migration, and invasion abilities of CC cells. Next, we verified that RPL34 regulated the CC through the MDM2‐P53 pathway by using Act D medicine, MDM2 inhibitor, and a series of western blotting（WB）assays. Moreover, an antisense lncRNA, RPL34‐AS1, regulated the expression of RPL34 and participated in the tumorigenesis of CC. RPL34 can reverse the effect of RPL34‐AS1 in CC cells. Finally, by RNA‐binding protein immunoprecipitation (RIP) assay we found that eukaryotic initiation factor 4A3 (EIF4A3), which binds to RPL34‐AS1, regulated RPL34‐AS1 expression in CC. Therefore, our findings indicate that RPL34‐AS1–induced RPL34 inhibits CC cell proliferation, invasion, and metastasis through modulation of the MDM2‐P53 signaling pathway, which provides a meaningful target for the early diagnosis and treatment of CC.