GAS5‑mediated regulation of cell signaling (Review).

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Abstract

In recent years, an increasing number of long non‑coding RNAs (lncRNAs) have been discovered using microarrays and nucleic acid sequencing technology. LncRNAs exert crucial biological functions by regulating signaling pathways. In particular, the lncRNA growth arrest‑specific transcript 5 (GAS5) has been documented to serve a crucial role in numerous signaling pathways. This article discusses the latest developments in the association between GAS5 and microRNA (miRNA), p53, mTOR, glucocorticoid response element (GRE) and AKT in order to investigate the roles served by GAS5. miRNAs can activate related signaling pathways and GAS5 can combine with miRNA to regulate related signaling pathways. GAS5 may regulate p53 expression via derivation of snoRNA, but the underlying mechanism requires further investigation. GAS5 overxpresion reduces the expression level of mTOR, which is induced by inhibiting miR‑106a‑5p expression. GAS5 is a sponge of GR, and serves a role in controlling and maintaining glucocorticoid sensitivity and drug resistance via competitive combination with GR. GAS5 can interact with miRNAs, such as miR‑21 and miR‑532‑5p, to regulate the expression of AKT signaling pathway, affecting cell survival and apoptosis. Collectively, the data indicate that GAS5 serves a key role in the miRNA, p53, mTOR, GRE, and AKT signaling pathways. GAS5 regulates complex intracellular signaling pathways primarily through three modes of action, all of which are interrelated: Signal, decoy and guide. In the present article, latest developments in the association between GAS5 and a number of cellular signaling pathways are discussed to examine the tumor suppressive role of GAS5.

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mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

Zhilin Zou, Tao Tao, Hongmei Li … (2020)

Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor field.

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Genes specifically expressed at growth arrest of mammalian cells.

C. Schneider, R. M. King, L Philipson (1988)

A subtraction cDNA library enriched for RNA sequences preferentially expressed in growth-arrested cells was prepared. Six cDNA clones were identified, varying in abundance from 2% to 0.0002% of the library and in size from 0.8 to 10 kb. The corresponding mRNAs are downregulated with different kinetics upon induction of growth by serum. The kinetics of induction after serum starvation and density-dependent inhibition of two of these growth-arrest-specific (gas) genes were investigated in more detail. Two cell lines transformed by viral onc genes did not express the two gas genes. The full-length cDNA for one gene has been sequenced and the protein product preliminarily characterized by in vitro translation.

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Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation.

L. Yan, J. Zhou, Y. Gao … (2015)

The imprinted, developmentally regulated H19 long noncoding RNA has been implicated in the pathogenesis of diverse human cancers, but the underlying mechanisms have remained poorly understood. Here, we report that H19 promotes tumor cell migration and invasion by inhibiting let-7, a potent tumor suppressor microRNA that functions to posttranscriptionally suppress the expression of oncogenes that regulate cell growth and motility. We show that H19 depletion impairs, whereas its overexpression enhances the motility and invasiveness of tumor cells. These phenomena occur, at least in part through affecting let-7-mediated regulation of metastasis-promoting genes, including Hmga2, c-Myc and Igf2bp3. This H19/let-7-dependent regulation is recapitulated in vivo where co-expressions of oncogenes and H19 exist in both primary human ovarian and endometrial cancers. Furthermore, we provide evidence that the anti-diabetic drug metformin inhibits tumor cell migration and invasion, partly by downregulating H19 via DNA methylation. Our results reveal a novel mechanism underpinning H19-mediated regulation in metastasis and may explain why in some cases increased let-7 expression unexpectedly correlates with poor prognosis, given the widely accepted role for let-7 as a tumor suppressor. Targeting this newly identified pathway might offer therapeutic opportunities.