Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma.
Down-Regulation of Long Non-Coding RNA TINCR Induces Cell Dedifferentiation and Predicts Progression in Oral Squamous Cell Carcinoma.
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长非编码 RNA TINCR 的下调诱导细胞去分化并预测口腔鳞状细胞癌的进展
DOI：
10.3389/fonc.2020.624752
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发表时间：
2020
影响因子：
4.7
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Zhuang Z;Huang J;Wang W;Wang C;Yu P;Hu J;Liu H;Yin H;Hou J;Liu X
目的 最近，长非编码 RNA (lncRNA) 已成为参与肿瘤发生过程（包括口腔鳞状细胞癌 (OSCC)）的新型基因调节因子。在这里，我们鉴定了一种分化相关的lncRNA，即终末分化诱导的非编码RNA（TINCR）。然而，其在 OSCC 中的生物学功能和临床病理意义仍不清楚。方法采用lncRNA芯片检测10例患者口腔鳞癌组织及配对的癌旁非肿瘤组织（NAT）中lncRNA的表达谱。进行加权基因共表达网络分析（WGCNA）和基因本体（GO）富集来分别识别最重要的模块和模块功能注释。通过差异表达分析筛选潜在分化相关的lncRNA。通过使用 qRT-PCR，TINCR 在另一个患者队列的 OSCC 细胞系和组织中得到了进一步证实。分析TINCR表达水平与临床病理特征的相关性。通过体外和体内敲低或敲入评估TINCR对细胞分化、迁移和侵袭的影响。结果WGCNA和GO富集分析显示，上皮细胞分化中有1个共表达网络显着富集，其中TINCR显着下调。 qRT-PCR分析证实，与配对的NAT相比，肿瘤组织中TINCR的表达下调，且其表达与OSCC患者的病理分化和淋巴结转移密切相关。 TINCR 表达水平较低的患者生存期较差。细胞功能实验表明TINCR在上皮分化中发挥着至关重要的作用。 TINCR 和上皮分化相关基因（包括 IVL 和 KRT4）在 OSCC 细胞钙诱导分化过程中显着上调，但当肿瘤球中发生细胞去分化时则下调。 TINCR的过表达在体外显着抑制细胞去分化、迁移和侵袭，而TINCR的敲低则具有相反的效果。 TINCR 的上调显着提高了终末分化基因的表达并抑制了体内肿瘤的生长。此外，TINCR 显着抑制 OSCC 细胞中 JAK2/STAT3 信号传导的激活。结论 我们的研究表明，TINCR 通过调节 OSCC 中的 JAK2/STAT3 信号传导来诱导细胞分化，从而发挥肿瘤抑制因子的作用。 TINCR 可作为 OSCC 的预后生物标志物和治疗靶点。
Objectives Recently long non-coding RNAs (lncRNAs) have emerged as novel gene regulators involved in tumorigenic processes, including oral squamous cell carcinoma (OSCC). Here, we identified a differentiation-related lncRNA, terminal differentiation-induced non-coding RNA (TINCR). However, its biological function and clinicopathological significance in OSCC still remain unclear. Methods The lncRNA expression profiles in OSCC tissues and paired adjacent non-tumor tissues (NATs) from 10 patients were detected by lncRNA microarrays. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) enrichment were performed to identify the most significant module and module functional annotation, respectively. Potential differentiation-related lncRNAs were screened by differential expression analysis. TINCR was further confirmed in OSCC cell lines and tissues of another patient cohort by using qRT-PCR. The correlation between the TINCR expression level and clinicopathological characteristics was analyzed. The effects of TINCR on cell differentiation, migration and invasion were assessed by knockdown or knock-in in vitro and in vivo. Results WGCNA and GO enrichment analysis showed that one co-expression network was significantly enriched for epithelial cell differentiation, among which, TINCR was significantly downregulated. qRT-PCR analyses validated down-regulation of TINCR in tumor tissues compared with paired NATs, and its expression was closely correlated with pathological differentiation and lymph node metastasis in patients with OSCC. Patients with lower TINCR expression levels had worse survival. Cell function experiments showed that TINCR played a crucial role in epithelial differentiation. Both TINCR and epithelial differentiation-associated genes, including IVL and KRT4, were significantly upregulated during OSCC cell calcium-induced differentiation but were reduced when cell dedifferentiation occurred in tumor spheres. Overexpression of TINCR dramatically suppressed cell dedifferentiation, migration and invasion in vitro, while knockdown of TINCR had the opposite effects. Upregulation of TINCR significantly elevated the expression of terminal differentiation genes and repressed tumor growth in vivo. Moreover, TINCR significantly suppressed the activation of JAK2/STAT3 signaling in OSCC cells. Conclusion Our study suggests that TINCR functions as a tumor suppressor by inducing cell differentiation through modulating JAK2/STAT3 signaling in OSCC. TINCR may serve as a prognostic biomarker and therapeutic target for OSCC.
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影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
影响因子：
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作者：
Chen Z;Liu Y;He A;Li J;Chen M;Zhan Y;Lin J;Zhuang C;Liu L;Zhao G;Huang W;Cai Z
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影响因子：
37.3
作者：
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通讯作者：
Han, Mingli
影响因子：
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作者：
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