Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway

Zhen,Yulan; Wu,Qiaomei; Ding,Yiqian; Zhang,Wei; Zhai,Yuansheng; Lin,Xiaoxiong; Weng,Yunxia; Guo,Ruixian; Zhang,Ying; Feng,Jianqiang; Lei,Yiyan; Chen,Jingfu

doi:10.3892/ol.2018.8154

Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway

Authors:
- Yulan Zhen
- Qiaomei Wu
- Yiqian Ding
- Wei Zhang
- Yuansheng Zhai
- Xiaoxiong Lin
- Yunxia Weng
- Ruixian Guo
- Ying Zhang
- Jianqiang Feng
- Yiyan Lei
- Jingfu Chen
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Affiliations: Department of Oncology, The Third People's Hospital of Dongguan Dongguan City, Guangdong 523326, P.R. China, Department of Anesthesiology, Oral Subsidiary Sun Yat‑Sen University Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510700, P.R. China, Grade 2013, Medical Imaging, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510000, P.R. China, Department of Cardiovasology and Cardiac Care Unit, Huangpu Division of The First Affiliated Hospital, Guangzhou, Guangdong 510080, P.R. China, Department of Physiology, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510700, P.R. China, Department of Oncology, Affiliated Hospital, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China, Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Cardiovascular Medicine and Dongguan Cardiovascular Institute, The Third People's Hospital of Dongguan City, Dongguan, Guangdong 523326, P.R. China
Published online on: March 2, 2018 https://doi.org/10.3892/ol.2018.8154
Pages: 6562-6570

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Abstract

The effects of hydrogen sulfide (H2S) on cancer are controversial. Our group previously demonstrated that exogenous H2S promotes the development of cancer via amplifying the activation of the nuclear factor‑κB signaling pathway in hepatocellular carcinoma (HCC) cells (PLC/PRF/5). The present study aimed to further investigate the hypothesis that exogenous H2S promotes PLC/PRF/5 cell proliferation and migration, and inhibits apoptosis by activating the signal transducer and activator of transcription 3 (STAT3)‑cyclooxygenase‑2 (COX‑2) signaling pathway. PLC/PRF/5 cells were treated with 500 µmol/l NaHS (a donor of H2S) for 24 h. The expression levels of phosphorylated (p)‑STAT3, STAT3, cleaved caspase‑3 and COX‑2 were measured by western blot assay. Cell viability was detected by Cell Counting kit‑8 assay. Apoptotic cells were observed by Hoechst 33258 staining. The expression of STAT3 and COX‑2 messenger RNA (mRNA) was detected by semiquantitative reverse transcription‑polymerase chain reaction. The production of vascular endothelial growth factor (VEGF) was evaluated by ELISA. The results indicated that treatment of PLC/PRF/5 cells with 500 µmol/l NaHS for 24 h markedly increased the expression levels of p‑STAT3 and STAT3 mRNA, leading to COX‑2 and COX‑2 mRNA overexpression, VEGF induction, decreased cleaved caspase‑3 production, increased cell viability and migration, and decreased number of apoptotic cells. However, co‑treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 30 µmol/l AG490 (an inhibitor of STAT3) or 20 µmol/l NS‑398 (an inhibitor of COX‑2) for 24 h significantly reverted the effects induced by NaHS. Furthermore, co‑treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 30 µmol/l AG490 markedly decreased the NaHS‑induced increase in the expression level of COX‑2. By contrast, co‑treatment of PLC/PRF/5 cells with 500 µmol/l NaHS and 20 µmol/l NS‑398 inhibited the NaHS‑induced increase in the expression level of p‑STAT3. In conclusion, the findings of the present study provide evidence that the STAT3‑COX‑2 signaling pathway is involved in NaHS‑induced cell proliferation, migration, angiogenesis and anti‑apoptosis in PLC/PRF/5 cells, and suggest that the positive feedback between STAT3 and COX-2 may serve a crucial role in hepatocellular carcinoma carcinogenesis.

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