Long non‐coding RNAs and TGF‐β signaling in cancer

Abstract

Cancer is driven by genetic mutations in oncogenes and tumor suppressor genes and by cellular events that develop a misregulated molecular microenvironment in the growing tumor tissue. The tumor microenvironment is guided by the excessive action of specific cytokines including transforming growth factor‐β (TGF‐β), which normally controls embryonic development and the homeostasis of young or adult tissues. As a consequence of the genetic alterations generating a given tumor, TGF‐β can preserve its homeostatic function and attempt to limit neoplastic expansion, whereas, once the tumor has progressed to an aggressive stage, TGF‐β can synergize with various oncogenic stimuli to facilitate tumor invasiveness and metastasis. TGF‐β signaling mechanisms via Smad proteins, various ubiquitin ligases, and protein kinases are relatively well understood. Such mechanisms regulate the expression of genes encoding proteins or non‐coding RNAs. Among non‐coding RNAs, much has been understood regarding the regulation and function of microRNAs, whereas the role of long non‐coding RNAs is still emerging. This article emphasizes TGF‐β signaling mechanisms leading to the regulation of non‐coding genes, the function of such non‐coding RNAs as regulators of TGF‐β signaling, and the contribution of these mechanisms in specific hallmarks of cancer.

<p>LncRNA LINC01116 Contributes to Cisplatin Resistance in Lung Adenocarcinoma</p>

“…LncRNAs are non-coding protein transcripts that have been proved to play a key regulatory role in tumorigenesis, metastasis, and chemotherapy resistance. [11][12][13][14] Increasing evidence has demonstrated the involvement of LncRNA in cisplatin resistance in multiple human cancers. [47][48][49][50][51] In NSCLC, LncRNA SPRY4-IT1 was reported to reverse cisplatin resistance partially through downregulating MPZL-1 via EMT, 52 and LncRNA NORAD was found to increase cisplatin resistance via the miR-129-1-3p/SOX4 axis.…”

“…Long non-coding RNA (lncRNA), a type of transcripts with greater than 200 nucleotides in length, has shown an important role in carcinogenesis and has been linked with cancer progression. [11][12][13] In addition, lncRNAs are found to be involved in chemotherapy resistance in multiple human cancers, including LAD. 14,15 LncRNA LINC01116, a novel lncRNA located on chromosome 2q31.1 with 838 nt in length, is reported to contribute to cancer progression.…”

The noncoding MIR100HG RNA enhances the autocrine function of transforming growth factor β signaling

“…One such pathway is transforming growth factor β (TGFβ) that signals via membrane receptors, which activate effector transcription factors (SMADs) and mitogen-activated protein kinases (MAPKs), to regulate target genes that control the cell cycle, migration, extracellular matrix remodeling, and epithelial–mesenchymal transition (EMT) [ 9 ]. Such target genes of TGFβ can be protein-coding or noncoding [ 10 ]. In normal or benign hyperplastic epithelial cells, TGFβ arrests the cell cycle and suppresses tumorigenesis by transcriptionally inducing the CDK inhibitors p15 Ink4b , p21 Cip1 , and p27 Kip1 , and repressing the proto-oncogene c-MYC [ 11 ].…”

Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway

“…Several miRNAs target either TβRs, Smads, or both, as negative regulators of TGF-β signaling. Long non-coding RNAs (lncRNAs) such as lncRNA-ATB, TUG1, lnc-TS-1, lnc-LFAR1, and TGFB2-AS1, participate in controlling either TGF-β-mediated EMT, fibrosis, or both, via their respective molecular functions [ 75 ]. Additionally, lncRNA ELIT-1 is induced by TGF-β and binds to Smad3 to facilitate recruitment to promoters of Smad target genes such as fibronectin, PAI-1, and Snail.…”