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CNOT7 depletion reverses natural killer cell resistance by modulating the tumor immune microenvironment of hepatocellular carcinoma.
FEBS Open Bio ( IF 2.6 ) Pub Date : 2020-04-02 , DOI: 10.1002/2211-5463.12836
Chongren Ren 1 , Xiaojing Ren 2 , Dujuan Cao 1 , Haichao Zhao 2 , Zhensheng Zhai 1 , Huiyu Li 1 , Yanjun Li 1 , Xifeng Fu 1 , Jiefeng He 1 , Haoliang Zhao 1
Affiliation  

A major obstacle to effective cancer immunotherapy is the tumor immune microenvironment. Natural killer (NK) cell resistance has been suggested as a primary cause of poor prognosis in hepatocellular carcinoma (HCC), which seemingly correlates with CNOT7 overexpression. CNOT7, a cytoplasmic mRNA deadenylase that is highly expressed in HCC, may regulate cytokine transforming growth factor‐β1 (TGF‐β1) secretion by controlling nuclear factor‐κB subunit p65 trafficking. CNOT7 depletion suppresses TGF‐β1 secretion in HCC and promotes interferon‐γ (IFN‐γ) secretion by NK cells, and we previously demonstrated that CNOT7 depletion reversed IFN‐γ resistance in HCC cells. Therefore, we hypothesized that CNOT7 depletion might reverse NK cell resistance by influencing the tumor immune microenvironment of HCC. To test this hypothesis, we examined the correlation between CNOT7, STAT1, TGF‐β1 and IFN‐γ expression with hepatitis B virus‐related cirrhosis and HCC with hepatitis B virus‐related cirrhosis. We found that modulation of CNOT7 expression alters TGF‐β1 secretion in HCC and IFN‐γ secretion in NK cells. We also examined the effects of NK cells in HepG2 cells with CNOT7 knockdown, which showed that NK cell surface CD107a expression is up‐regulated and caspase‐3 expression is significantly enhanced in CNOT7‐deficient HepG2 cells. Overall, our results show that knockdown of CNOT7 expression reverses NK cell resistance in HCC cells. Therefore, CNOT7 depletion has potential as a new adjuvant therapy in immunotherapy for HCC.

中文翻译:

CNOT7耗竭通过调节肝细胞癌的肿瘤免疫微环境来逆转自然杀伤细胞的抵抗力。

有效的癌症免疫疗法的主要障碍是肿瘤免疫微环境。天然杀伤(NK)细胞耐药性已被认为是肝细胞癌(HCC)预后不良的主要原因,这似乎与CNOT7过表达有关。CNOT7是在肝癌中高表达的胞质mRNA腺苷酸酶,可通过控制核因子κB亚基p65的运输来调节细胞因子转化生长因子β1(TGF-β1)的分泌。CNOT7耗竭抑制HCC中TGF-β1的分泌并促进NK细胞分泌IFN-γ(IFN-γ),我们以前证明CNOT7耗竭可以逆转HCC细胞中的IFN-γ抗性。因此,我们假设CNOT7耗竭可能通过影响HCC的肿瘤免疫微环境而逆转NK细胞耐药性。为了检验这个假设,我们检查了CNOT7,STAT1,TGF-β1和IFN-γ表达与乙肝病毒相关性肝硬化和HCC与乙肝病毒相关性肝硬化之间的相关性。我们发现,调节CNOT7的表达会改变HCC中的TGF-β1分泌和NK细胞中的IFN-γ分泌。我们还检查了NK细胞在HepG2细胞中的作用CNOT7敲低表明,在CNOT7缺失的HepG2细胞中,NK细胞表面CD107a表达被上调,而caspase-3表达则显着增强。总体而言,我们的结果表明,敲低CNOT7表达可逆转HCC细胞中的NK细胞耐药性。因此,CNOT7耗竭作为HCC免疫治疗的新辅助疗法具有潜力。
更新日期:2020-04-02
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