PMID- 31619254 OWN - NLM STAT- MEDLINE DCOM- 20200813 LR - 20231213 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 17 IP - 1 DP - 2019 Oct 16 TI - PYCR1 interference inhibits cell growth and survival via c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathway in hepatocellular cancer. PG - 343 LID - 10.1186/s12967-019-2091-0 [doi] LID - 343 AB - BACKGROUND: Liver cancer is the second leading causes of cancer-related death globally. Pyrroline-5-carboxylate reductase 1 (PYCR1) plays a critical role in metabolic profiles of tumors. Therefore, it is necessary to explore the mechanisms of PYCR1 on cell growth and survival in hepatocellular carcinoma (HCC). METHODS: Protein and mRNA expression levels of PYCR1 in 140 pairs of tumor and adjacent normal liver tissues of HCC patients were analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Expressions of PYCR1 were inhibited in BEL-7404 cells and SMMC-7721 cells using gene interference technology. The cell proliferation was detected by Celigo and MTT assay. The colony formation assay was also performed. The cell apoptosis was measured by flow cytometric assay. The effect of PYCR1 interference on tumor growth was observed by xenograft nude mice assay in vivo. The downstream pathway of PYCR1 interference was searched by microarray and bioinformatics analysis, and validated by qRT-PCR and western blot. RESULTS: PYCR1 levels were significantly up-regulated in HCC tumor tissues than adjacent normal liver tissues in both protein and mRNA levels (P < 0.01). In vitro, the cell proliferation was significantly slower in shPYCR1 group than shCtrl group in BEL-7404 and SMMC-7721 cells (P < 0.001). The colony number was significantly smaller after PYCR1 interference (P < 0.01). The percentage of apoptosis cells significantly increased in shPYCR1 group (P < 0.01). In vivo, PYCR1 interference could obviously suppress tumor growth in xenograft nude mice. The volume and weight of tumors were significantly smaller via PYCR1 interference. The c-Jun N-terminal kinase (JNK) signaling pathway significantly altered, and insulin receptor substrate 1 (IRS1) were significantly down-regulated by PYCR1 interference in both mRNA and protein levels (P < 0.001). CONCLUSION: PYCR1 interference could inhibit cell proliferation and promote cell apoptosis in HCC through regluting JNK/IRS1 pathway. Our study will provide a drug target for HCC therapy and a potential biomarker for its diagnosis or prognosis. FAU - Zhuang, Juhua AU - Zhuang J AD - Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. FAU - Song, Yanan AU - Song Y AD - Central Laboratory, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. FAU - Ye, Ying AU - Ye Y AD - Central Laboratory, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. FAU - He, Saifei AU - He S AD - Central Laboratory, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. FAU - Ma, Xing AU - Ma X AD - Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. FAU - Zhang, Miao AU - Zhang M AD - Central Laboratory, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. FAU - Ni, Jing AU - Ni J AD - Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. FAU - Wang, Jiening AU - Wang J AD - Central Laboratory, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. ynsong_12345@126.com. FAU - Xia, Wei AU - Xia W AD - Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, Pudong, Shanghai, 200137, People's Republic of China. awingxia@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191016 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (IRS1 protein, human) RN - 0 (Insulin Receptor Substrate Proteins) RN - EC 1.5.1.- (Pyrroline Carboxylate Reductases) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Apoptosis MH - Carcinoma, Hepatocellular/genetics/*pathology MH - Cell Line, Tumor MH - Cell Proliferation MH - Cell Survival MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Insulin Receptor Substrate Proteins/*metabolism MH - JNK Mitogen-Activated Protein Kinases/*metabolism MH - Liver Neoplasms/genetics/*pathology MH - Mice, Inbred BALB C MH - Mice, Nude MH - Models, Biological MH - Pyrroline Carboxylate Reductases/*metabolism MH - *Signal Transduction MH - delta-1-Pyrroline-5-Carboxylate Reductase PMC - PMC6796468 OTO - NOTNLM OT - Hepatocellular carcinoma OT - IRS1 OT - Insulin resistance OT - JNK OT - PYCR1 COIS- The authors declare that they have no competing interests. EDAT- 2019/10/18 06:00 MHDA- 2020/08/14 06:00 PMCR- 2019/10/16 CRDT- 2019/10/18 06:00 PHST- 2019/05/05 00:00 [received] PHST- 2019/10/05 00:00 [accepted] PHST- 2019/10/18 06:00 [entrez] PHST- 2019/10/18 06:00 [pubmed] PHST- 2020/08/14 06:00 [medline] PHST- 2019/10/16 00:00 [pmc-release] AID - 10.1186/s12967-019-2091-0 [pii] AID - 2091 [pii] AID - 10.1186/s12967-019-2091-0 [doi] PST - epublish SO - J Transl Med. 2019 Oct 16;17(1):343. doi: 10.1186/s12967-019-2091-0.