PMID- 30562757 OWN - NLM STAT- MEDLINE DCOM- 20190129 LR - 20190212 IS - 1421-9778 (Electronic) IS - 1015-8987 (Linking) VI - 51 IP - 6 DP - 2018 TI - High Expressions of CUL4A and TP53 in Colorectal Cancer Predict Poor Survival. PG - 2829-2842 LID - 10.1159/000496013 [doi] AB - BACKGROUND/AIMS: Cullin 4A (CUL4A) is vital in cell survival, development, growth and cell cycle, it plays an important role in chaperone-mediated ubiquitination and interacts with TP53 in carcinogenesis. However, the clinicopathologic significance of CUL4A expression in colorectal cancer is unknown; in particular, the prognostic value of CUL4A combined with TP53 expression has not been explored. METHODS: We analyzed the expression of CUL4A in both public database (Oncomine) and 180 cases of colorectal cancer and paired normal tissues by real-time polymerase chain reaction and western blotting. Colony formation, wound healing, migration and invasion assays and tumorigenesis in nude mice were used to explore the function of CUL4A in CRC proliferation and metastasis in vitro and in vivo. Markers of epithelial to mesenchymal transition (EMT) were evaluated by western blotting. Immunohistochemistry (IHC) was used to analyse the relationship between CUL4A expression and E-cadherin expression. RESULTS: CUL4A and TP53 protein expression was significantly higher in cancerous tissues compared to normal tissues. Significant correlation between CUL4A and TP53 expression was observed. CUL4A expression was an independent prognostic factor for overall survival (OS) and disease-free survival (DFS). Interestingly, patients with tumors that had both CUL4A overexpression and mutant TP53 protein accumulation relapsed and died within a significantly short period after surgery (P < 0.001). Multivariate analysis showed that patients with both CUL4A+ and TP53+ positive tumors had extremely poor OS and DFS. Knockdown of CUL4A by a short interfering RNA (siRNA) significantly suppressed the progression of EMT, proliferation, migration, and invasion of colon cancer cells in vitro and tumor growth in vivo. ZEB1 silencing blocked CUL4A-driven these processes. CONCLUSION: CUL4A expression correlated positively with the prognosis of colorectal cancer. Mechanistically, ZEB1 was confirmed to mediate the function of CUL4A in regulating the EMT. The assessment of both CUL4A and mutant TP53 expression will be helpful in predicting colon cancer prognosis. CI - (c) 2018 The Author(s). Published by S. Karger AG, Basel. FAU - Li, Chao AU - Li C AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Bu, Juyuan AU - Bu J AD - Department of gastrointestinal surgery, the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. FAU - Liao, Yifeng AU - Liao Y AD - Department of abdominal chemotherapy, the Fifth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. FAU - Zhang, Jin AU - Zhang J AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Han, Jun AU - Han J AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Zhang, Han AU - Zhang H AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Xing, Hao AU - Xing H AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Li, Zhenli AU - Li Z AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Wu, Han AU - Wu H AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Liang, Lei AU - Liang L AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Wang, Mingda AU - Wang M AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. FAU - Qin, Wenxing AU - Qin W AD - Department of Clinical Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China. FAU - Yang, Tian AU - Yang T AD - Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, Chinayangtiandfgd@hotmail.com. LA - eng PT - Journal Article DEP - 20181218 PL - Germany TA - Cell Physiol Biochem JT - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology JID - 9113221 RN - 0 (CUL4A protein, human) RN - 0 (Cullin Proteins) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) SB - IM MH - Aged MH - Animals MH - Cell Line, Tumor MH - Colon/metabolism/pathology MH - Colorectal Neoplasms/diagnosis/*genetics/pathology MH - Cullin Proteins/analysis/*genetics MH - Epithelial-Mesenchymal Transition MH - Female MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Male MH - Mice, Nude MH - Middle Aged MH - Neoplasm Invasiveness/diagnosis/genetics/pathology MH - Prognosis MH - Rectum/metabolism/pathology MH - Tumor Suppressor Protein p53/analysis/*genetics MH - *Up-Regulation OTO - NOTNLM OT - CUL4A OT - Colorectal cancer OT - EMT OT - Prognosis OT - ZEB1 EDAT- 2018/12/19 06:00 MHDA- 2019/01/30 06:00 CRDT- 2018/12/19 06:00 PHST- 2017/09/26 00:00 [received] PHST- 2018/12/05 00:00 [accepted] PHST- 2018/12/19 06:00 [pubmed] PHST- 2019/01/30 06:00 [medline] PHST- 2018/12/19 06:00 [entrez] AID - 000496013 [pii] AID - 10.1159/000496013 [doi] PST - ppublish SO - Cell Physiol Biochem. 2018;51(6):2829-2842. doi: 10.1159/000496013. Epub 2018 Dec 18.