Signaling in and out: long-noncoding RNAs in tumor hypoxia

Abstract

Over the past few years, long non-coding RNAs (lncRNAs) are recognized as key regulators of gene expression at chromatin, transcriptional and posttranscriptional level with pivotal roles in various biological and pathological processes, including cancer. Hypoxia, a common feature of the tumor microenvironment, profoundly affects gene expression and is tightly associated with cancer progression. Upon tumor hypoxia, the central regulator HIF (hypoxia-inducible factor) is upregulated and orchestrates transcription reprogramming, contributing to aggressive phenotypes in numerous cancers. Not surprisingly, lncRNAs are also transcriptional targets of HIF and serve as effectors of hypoxia response. Indeed, the number of hypoxia-associated lncRNAs (HALs) identified has risen sharply, illustrating the expanding roles of lncRNAs in hypoxia signaling cascade and responses. Moreover, through extra-cellular vesicles, lncRNAs could transmit hypoxia responses between cancer cells and the associated microenvironment. Notably, the aberrantly expressed cellular or exosomal HALs can serve as potential prognostic markers and therapeutic targets. In this review, we provide an update of the current knowledge about the expression, involvement and potential clinical impact of lncRNAs in tumor hypoxia, with special focus on their unique molecular regulation of HIF cascade and hypoxia-induced malignant progression.

Association of cyclin-dependent kinase inhibitor 2B antisense RNA 1 gene expression and rs2383207 variant with breast cancer risk and survival

“…CDKN2B-AS1 abundance can also be induced by exposure to hypoxia (a well-known phenomenon associated with the tumor microenvironment). It can bind the aryl hydrocarbon receptor nuclear translocator (ARNT), which functions as a transcriptional regulator of the adaptive response to hypoxia [ 48 ]. Apart from the potential oncogenic role of CDKN2B-AS1 in BC, all the above mechanisms could support CDKN2B-AS1 upregulation in breast cancer in part as an adaptive response to DNA and cellular damage during the tumorigenesis process, which could explain the association of high expression of this type of lncRNA with survival and cancer grade; the findings were validated by the same results from the TCGA data set.…”

A pair of long intergenic non-coding RNA LINC00887 variants act antagonistically to control Carbonic Anhydrase IX transcription upon hypoxia in tongue squamous carcinoma progression

“…It would be of great interest to investigate how the dynamic interaction between these two RNAs is regulated in the future. LncRNAs are highly sensitive to their cellular environment [ 77 ]. It is very likely that certain hypoxia-triggered microenvironment alterations (e.g., pH) induce the signal-specific higher structural changes of either RNA variant or both to modulate their RNA-RNA interaction status, each RNA’s binding ability to the corresponding cis-acting element and thus their regulation on CA9 expression.…”

Association of rs3746444 in MiRNA-499 and rs3787016 in Long Non-coding RNAs POLR2E with Prostate Cancer: an updated meta-analysis and systematic review

“…Rs3787016, localizes to the fourth intron of RNA polymerase II polypeptide E (POLR2E) 16 gene, has been investigated by several researchers on its association with cancer risk [16,[30][31][32][33][34][35][36][37].The most important function of LncRNAs is involvement in the transcriptional or posttranscriptional regulation of gene expression [38]. Abnormal expressions of these RNAs facilitate tumor-cell proliferation, invasion and survival in cancer development and progression [39][40][41]. There is a tremendous amount of developmental biological mechanisms of LncRNAs function in cancer that is unclaimed by most of existing theories.…”