title: Gain-of-function miRNA signature by mutant p53 associates with poor cancer outcome.
abstract: Missense mutation of p53 not only impairs its tumor suppression function, but also causes oncogenic gain of function (GOF). The molecular underpinning of mutant p53 (mutp53) GOF is not fully understood, especially for the potential roles of non-coding genes. Here we identify the microRNA expression profile (microRNAome) of mutp53 on Arg282 by controlled microarray experiments, and clarify the prognostic significance of mutp53-regulated miRNAs in cancers. A predominant repression effect on miRNA expression was found for mutant p53, with 183 significantly downregulated and only 12 upregulated miRNAs. Mutp53 and wild-type (wtp53) commonly upregulate let-7i, and other two miRNAs were upregulated by wtp53 but repressed by mutp53 (miR-610 and miR-3065-3p). Based the mutp53-regulated miRNA signature, a non-negative matrix factorization (NMF) model classified gastric cancer (GC) cases into subgroups with significantly different Disease-free survival (Kaplan-Meier test, P = 0.013). In contrast, the NMF model based on all miRNAs did not associate with cancer outcome. The mutp53 miRNA signature associated with the outcomes of breast cancer (P = 0.024) and hepatocellular cancer (P = 0.012). The miRPath analysis revealed that mutp53-suppressed miRNAs associate with Hippo, TGF-β and stem cell signaling pathways. Taken together, our results highlight a miRNA-mediated GOF mechanism of mutant p53 on Arg282, and suggest the prognostic potential of mutp53-associated miRNA signature.
authors: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, China.
authors: Yao
authors: Y
authors: Zhang
authors: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, China.|Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors: Ye
authors: Y
authors: Hu
authors: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, China.
authors: Jing-Yuan
authors: JY
authors: Fang
authors: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, China.
authors: Jie
authors: J
authors: Xu
mesh_terms: D016000:Cluster Analysis; D018572:Disease-Free Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics*; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: cancer prognosis; miRNA; mutation; non-negative matrix factorization; p53