CRISPR/Cas9‑mediated hypoxia inducible factor‑1α knockout enhances the antitumor effect of transarterial embolization in hepatocellular carcinoma

Liu,Quan; Fan,Dahua; Adah,Dickson; Wu,Zhengzhi; Liu,Renyan; Yan,Qiao‑Ting; Zhang,Yue; Du,Zhi‑Yong; Wang,Dou; Li,Yan; Bao,Shi‑Yun; Liu,Li‑Ping

doi:10.3892/or.2018.6667

CRISPR/Cas9‑mediated hypoxia inducible factor‑1α knockout enhances the antitumor effect of transarterial embolization in hepatocellular carcinoma

Authors:
- Quan Liu
- Dahua Fan
- Dickson Adah
- Zhengzhi Wu
- Renyan Liu
- Qiao‑Ting Yan
- Yue Zhang
- Zhi‑Yong Du
- Dou Wang
- Yan Li
- Shi‑Yun Bao
- Li‑Ping Liu
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Affiliations: Department of Hepatobiliary and Pancreas Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R. China, Department of Chinese and Western Integrative Medicine, The Eighth Affiliated Hospital of Sun Yat‑Sen University, Shenzhen, Guangdong 518033, P.R. China, University of Chinese Academy of Sciences, Beijing 100049, P.R. China, Department of Chinese and Western Integrative Medicine, The Eighth Affiliated Hospital of Sun Yat‑Sen University, Shenzhen, Guangdong 518033, P.R. China, Department of Pharmacology, Upstate Medical University, State University of New York, Syracuse, NY 13210, USA, Department of Hepatobiliary and Pancreas Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R. China
Published online on: August 23, 2018 https://doi.org/10.3892/or.2018.6667
Pages: 2547-2557
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Transarterial embolization (TAE) is a palliative option commonly used for the treatment of advanced, unresectable hepatocellular carcinoma (HCC). However, patient prognosis in regards to overall survival has not improved with this method, mainly due to hypoxia‑inducible factor‑1α (HIF‑1α)‑induced angiogenesis and invasiveness. Thus, it is hypothesized that HIF‑1α may be an ideal knockout target for the treatment of HCC in combination with TAE. Thus, in the present study, HIF‑1α knockout was conducted in human liver cancer SMMC‑7721 cells and a xenograft HCC model was established using a lentivirus‑mediated CRISPR/Cas system (LV‑Cas) with small guide RNA‑721 (LV‑H721). Furthermore, hepatic artery ligation (HAL) was used to mimic human transarterial chemoembolization in mice. The results revealed that HIF‑1α was highly expressed in both HCC patient tissues and SMMC‑7721‑induced tumor tissues. The HIF‑1α knockout in SMMC‑7721 cells significantly suppressed cell invasiveness and migration, and induced cell apoptosis under CoCl2‑mimicking hypoxic conditions. Compared with the control groups, HAL + LV‑H721 inhibited SMMC‑7721 tumor growth in orthotopic HCC and markedly prolonged the survival of HCC‑bearing mice, which was accompanied by a lower CD31 expression (tumor angiogenesis) and increased apoptosis in the tumor cells. These findings demonstrated a valuable antitumor synergism in combining CRISPR/Cas9‑mediated HIF‑1α knockout with TAE in mice and highlighted the possibility that HIF‑1α may be an effective therapeutic knockout target in combination with TAE for HCC treatment.

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