LncRNA TINCR favors tumorigenesis via STAT3-TINCR-EGFR-feedback loop by recruiting DNMT1 and acting as a competing endogenous RNA in human breast cancer.
LncRNA TINCR favors tumorigenesis via STAT3-TINCR-EGFR-feedback loop by recruiting DNMT1 and acting as a competing endogenous RNA in human breast cancer.
复制标题
LncRNA TINCR 通过 STAT3-TINCR-EGFR 反馈环路招募 DNMT1 并充当人类乳腺癌中的竞争性内源性 RNA，有利于肿瘤发生
DOI：
10.1038/s41419-020-03188-0
复制
发表时间：
2021-01-14
影响因子：
9
通讯作者：
Pang D
中科院分区：
文献类型：
--
作者：
Wang Q;Liu J;You Z;Yin Y;Liu L;Kang Y;Li S;Ning S;Li H;Gong Y;Xu S;Pang D
最近发现长链非编码RNA（lncRNA）TINCR与人类恶性肿瘤的进展相关，但TINCR作用的分子机制仍然难以捉摸，特别是在乳腺癌中。在体外和体内研究了TINCR在乳腺癌中的致癌作用。接下来，探索了TINCR、DNMT 1和miR-503- 5 p甲基化之间的相互作用。此外，全面研究了TINCR通过RNA-RNA相互作用增强EGFR表达和下游信号传导的机制。此外，上游转录调控TINCR表达的STAT 3进行染色质免疫沉淀检查。最后，还研究了STAT 3-TINCR-EGFR下游级联中的反馈信号传导。TINCR在人乳腺癌组织中上调，TINCR敲低抑制体外和体内肿瘤发生。从机制上讲，TINCR将DNMT 1募集到miR-503- 5 p基因座启动子上，从而增加甲基化并抑制miR-503- 5 p的转录表达。此外，TINCR还作为竞争性内源性RNA发挥作用，通过海绵化miR-503- 5 p上调EGFR表达。此外，TINCR刺激EGFR下游的JAK 2-STAT 3信号传导，并且STAT 3 β增强TINCR的转录表达。我们的发现拓宽了目前对TINCR在癌症生物学中发挥作用的不同方式的理解。新发现的STAT 3-TINCR-EGFR-反馈环可以作为人类癌症的潜在治疗靶点。
The long noncoding RNA (lncRNA) TINCR has recently been found to be associated with the progression of human malignancies, but the molecular mechanism of TINCR action remains elusive, particularly in breast cancer. The oncogenic role of TINCR was examined in vitro and in vivo in breast cancer. Next, the interaction between TINCR, DNMT1, and miR-503-5p methylation was explored. Moreover, the mechanism by which TINCR enhances EGFR expression and downstream signaling via an RNA–RNA interaction was comprehensively investigated. Furthermore, upstream transcriptional regulation of TINCR expression by STAT3 was examined by performing chromatin immunoprecipitation. Finally, feedback signaling in the STAT3–TINCR–EGFR downstream cascade was also investigated. TINCR is upregulated in human breast cancer tissues, and TINCR knockdown suppresses tumorigenesis in vitro and in vivo. Mechanistically, TINCR recruits DNMT1 to the miR-503-5p locus promoter, which increases the methylation and suppresses the transcriptional expression of miR-503-5p. Furthermore, TINCR also functions as a competing endogenous RNA to upregulate EGFR expression by sponging miR-503-5p. In addition, TINCR stimulates JAK2–STAT3 signaling downstream from EGFR, and STAT3 reciprocally enhances the transcriptional expression of TINCR. Our findings broaden the current understanding of the diverse manners in which TINCR functions in cancer biology. The newly identified STAT3–TINCR–EGFR-feedback loop could serve as a potential therapeutic target for human cancer.
登录
查看更多内容
影响因子：
4.3
作者：
Bai, Jinghui;Xu, Jian;Zhang, Rui
通讯作者：
Zhang, Rui
影响因子：
8.8
作者：
Citro, Simona;Bellini, Alice;Chiocca, Susanna
通讯作者：
Chiocca, Susanna
影响因子：
11.5
作者：
Hwang, Ki-Tae;Kim, Jongjin;Hwang, Kyu Ri
通讯作者：
Hwang, Kyu Ri
影响因子：
64.8
作者：
Munschauer, Mathias;Nguyen, Celina T.;Lander, Eric S.
通讯作者：
Lander, Eric S.
影响因子：
5.6
作者：
Mallmann-Gottschalk, Nina;Sax, Yvonne;Brandau, Sven
通讯作者：
Brandau, Sven