HNRNPC downregulation inhibits IL-6/STAT3-mediated HCC metastasis by decreasing HIF1A expression.
HNRNPC downregulation inhibits IL-6/STAT3-mediated HCC metastasis by decreasing HIF1A expression.
复制标题
HNRNPC 下调通过降低 HIF1A 表达抑制 IL‐6/STAT3‐介导的 HCC 转移
作者：
RNA结合蛋白（RBP）失调在功能上与几种人类疾病有关，包括神经系统疾病，心血管疾病和癌症。异质核核糖核蛋白（hnRNP）是参与核酸代谢的不同家族的RBP。越来越多的研究表明，hnRNP的异常调节在肿瘤发生中发挥重要作用。本研究通过生物信息学分析，发现异质核核糖核蛋白C（C1/C2）（HNRNPC）在区分肝细胞癌（HCC）和正常肝组织方面具有良好的性能。进一步的研究显示，HNRNPC与HCC的多种恶性特征，包括肿瘤大小、微血管浸润、肿瘤分化和TNM分期显著相关。HNRNPC阳性表达的HCC患者的总生存率降低，复发率增加。HNRNPC下调可抑制HCC的侵袭和转移。缺氧诱导因子1 α亚基（HIF 1A）表达的降低被确定为HNRNPC下调抑制HCC转移的分子机制。机制上，HNRNPC下调通过破坏HIF 1A mRNA的稳定来降低HIF 1A的表达。HIF 1A过表达可挽救HNRNPC下调引起的HCC侵袭和转移的降低。此外，白细胞介素（IL）-6/STAT3信号转导上调HCC细胞中的HNRNPC表达，并且HNRNPC的敲低显著抑制IL-6/STAT 3增强的HCC转移。此外，抗IL-6抗体siltuximab显著抑制IL-6介导的HCC转移。总之，我们的研究揭示了HNRNPC在HCC中的临床价值、功能作用和分子机制，并显示了HNRNPC作为HCC诊断、预后和进一步治疗靶点的生物标志物的潜力。Siltuximab阻断了IL-6/STAT 3介导的HNRNPC的转录激活，然后微弱的HNRNPC不能与HIF 1A mRNA结合，使HIF 1A mRNA不稳定并降解，从而抑制HCC转移。
RNA‐binding protein (RBP) dysregulation is functionally linked to several human diseases, including neurological disorders, cardiovascular disease, and cancer. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RBPs involved in nucleic acid metabolism. A growing body of studies has shown that the dysregulated hnRNPs play important roles in tumorigenesis. Here, we found that heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRNPC) had good performance in distinguishing between hepatocellular carcinoma (HCC) and normal liver tissues through bioinformatics analysis. Further investigation revealed that HNRNPC was significantly correlated with multiple malignant characteristics of HCC, including tumor size, microvascular invasion, tumor differentiation, and TNM stage. Patients with HCC with positive HNRNPC expression exhibited decreased overall survival and increased recurrence rate. HNRNPC downregulation inhibited HCC invasion and metastasis. The decreased expression of hypoxia inducible factor 1 subunit alpha (HIF1A) was identified as the molecular mechanism underlying HNRNPC downregulation‐inhibited HCC metastasis by RNA sequencing. Mechanistically, HNRNPC downregulation decreased HIF1A expression by destabilizing HIF1A mRNA. HIF1A overexpression rescued the decrease in invasiveness and metastasis of HCC induced by HNRNPC downregulation. Additionally, interleukin (IL)‐6/STAT3 signaling upregulated HNRNPC expression in HCC cells, and knockdown of HNRNPC significantly inhibited IL‐6/STAT3‐enhanced HCC metastasis. Furthermore, anti‐IL‐6 antibody siltuximab significantly inhibited IL‐6‐mediated HCC metastasis. In summary, our research revealed the clinical value, functional role, and molecular mechanism of HNRNPC in HCC and showed the potential of HNRNPC as a biomarker for diagnosis, prognosis, and further therapeutic targets for HCC. Siltuximab blocks IL‐6/STAT3‐mediated transcriptional activation of HNRNPC, and then faint HNRNPC is incapable of binding to HIF1A mRNA, which makes HIF1A mRNA unstable and degraded, thus inhibiting HCC metastasis.
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影响因子：
9
作者：
Guo E;Mao X;Wang X;Guo L;An C;Zhang C;Song K;Wang G;Duan C;Zhang X;Yang X;Yuan Z;Sun J;Li X;Yang W;Meng H;Miao S
通讯作者：
Miao S
DOI：
10.1084/jem.20201833
发表时间：
2021-09-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Herzner AM;Khan Z;Van Nostrand EL;Chan S;Cuellar T;Chen R;Pechuan-Jorge X;Komuves L;Solon M;Modrusan Z;Haley B;Yeo GW;Behrens TW;Albert ML
通讯作者：
Albert ML
影响因子：
64.5
作者：
Liu J;Lichtenberg T;Hoadley KA;Poisson LM;Lazar AJ;Cherniack AD;Kovatich AJ;Benz CC;Levine DA;Lee AV;Omberg L;Wolf DM;Shriver CD;Thorsson V;Cancer Genome Atlas Research Network;Hu H
通讯作者：
Hu H
影响因子：
11.1
作者：
Li, Fei;Zhao, Hongfan;Tan, Wanlong
通讯作者：
Tan, Wanlong
影响因子：
78.8
作者：
Crusz, Shanthini M.;Balkwill, Frances R.
通讯作者：
Balkwill, Frances R.