长链非编码 RNA TINCR 通过调控 miR-195-3p/ST6GAL1/NF-κB 通路促进肝癌进展并降低奥沙利铂化疗敏感性。

Long noncoding RNA TINCR facilitates hepatocellular carcinoma progression and dampens chemosensitivity to oxaliplatin by regulating the miR-195-3p/ST6GAL1/NF-κB pathway.

机构信息

Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

出版信息

J Exp Clin Cancer Res. 2022 Jan 3;41(1):5. doi: 10.1186/s13046-021-02197-x.

BACKGROUND

Long non-coding RNAs (lncRNA) have an essential role in progression and chemoresistance of hepatocellular carcinoma (HCC). In-depth study of specific regulatory mechanisms is of great value in providing potential therapeutic targets. The present study aimed to explore the regulatory functions and mechanisms of lncRNA TINCR in HCC progression and oxaliplatin response.

METHODS

The expression of TINCR in HCC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration, invasion, and chemosensitivity were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and apoptosis assays. Luciferase reporter assays and RNA pulldown were used to identify the interaction between TINCR and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) via miR-195-3p. The corresponding functions were verified in the complementation test and in vivo animal experiment.

RESULTS

TINCR was upregulated in HCC and associated with poor patient prognosis. Silencing TINCR inhibited HCC proliferation, migration, invasion, and oxaliplatin resistance while overexpressing TINCR showed opposite above-mentioned functions. Mechanistically, TINCR acted as a competing endogenous (ceRNA) to sponge miR-195-3p, relieving its repression on ST6GAL1, and activated nuclear factor kappa B (NF-κB) signaling. The mouse xenograft experiment further verified that knockdown TINCR attenuated tumor progression and oxaliplatin resistance in vivo.

CONCLUSIONS

Our finding indicated that there existed a TINCR/miR-195-3p/ST6GAL1/NF-κB signaling regulatory axis that regulated tumor progression and oxaliplatin resistance, which might be exploited for anticancer therapy in HCC.

背景

长链非编码 RNA（lncRNA）在肝细胞癌（HCC）的进展和化疗耐药中发挥重要作用。深入研究特定的调控机制对于提供潜在的治疗靶点具有重要价值。本研究旨在探讨 lncRNA TINCR 在 HCC 进展和奥沙利铂反应中的调控作用和机制。

方法

采用实时定量逆转录 PCR（qRT-PCR）检测 TINCR 在 HCC 组织和细胞系中的表达。通过细胞计数试剂盒 8（CCK8）、集落形成、Transwell 和凋亡实验评估细胞增殖、迁移、侵袭和化疗敏感性。通过荧光素酶报告基因实验和 RNA 下拉实验鉴定 TINCR 与 ST6β-半乳糖苷α-2,6-唾液酸转移酶 1（ST6GAL1）通过 miR-195-3p 相互作用。通过互补试验和体内动物实验验证相应的功能。

结果

TINCR 在 HCC 中上调，并与患者预后不良相关。沉默 TINCR 抑制 HCC 增殖、迁移、侵袭和奥沙利铂耐药，而过表达 TINCR 则表现出相反的上述功能。机制上，TINCR 作为竞争性内源性 RNA（ceRNA），可吸附 miR-195-3p，解除其对 ST6GAL1 的抑制作用，激活核因子 κB（NF-κB）信号通路。小鼠异种移植实验进一步验证了沉默 TINCR 可减弱体内肿瘤进展和奥沙利铂耐药。