Abstract
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.
Highlights
Introduction Long noncodingRNAs are >200-nt-longRNA transcripts encoded by the genome that are mostly not translated into proteins, but play key roles in regulating gene expression, chromatin dynamics, differentiation, growth, and development[1,2]
TINCR expression is upregulated and correlated with poor prognosis in breast cancer By using the large-scale cancer-genome RNA-seq expression data from The Cancer Genome Atlas (TCGA) database, we examined the potential association of carcinogenesis with the long noncoding RNA (lncRNA) differentially expressed between breast-cancer and adjacent normal tissues (Fig. 1a, b)
We focused on TINCR, which was found to be expressed at higher levels in human breast-cancer than in normal tissues (Fig. 1c, d)
Summary
RNA transcripts encoded by the genome that are mostly not translated into proteins, but play key roles in regulating gene expression, chromatin dynamics, differentiation, growth, and development[1,2]. Several lncRNAs are aberrantly expressed in cancers and can serve as lncRNAs whose aberrant expression is associated with different cancer types, including breast, pancreatic, lung, liver, gastric, head and neck, and colon cancers[6,7,8,9,10,11,12]. LncRNAs have been recognized as fundamental regulators of gene expression, most lncRNAs remain functionally uncharacterized in cancer. Breast cancer (BC) is the most common female malignant tumor worldwide. A major feature is its challenging heterogeneity at the clinical and molecular level[13].
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