Abstract
Hypoxia is a classic characteristic of the tumor microenvironment with a significant impact on cancer progression and therapeutic response. Hypoxia-inducible factor-1 alpha (HIF-1α), the most important transcriptional regulator in the response to hypoxia, has been demonstrated to significantly modulate hypoxic gene expression and signaling transduction networks. In past few decades, growing numbers of studies have revealed the importance of noncoding RNAs (ncRNAs) in hypoxic tumor regions. These hypoxia-responsive ncRNAs (HRNs) play pivotal roles in regulating hypoxic gene expression at the transcriptional, posttranscriptional, translational and posttranslational levels. In addition, as a significant gene expression regulator, ncRNAs exhibit promising roles in regulating HIF-1α expression at multiple levels. In this review, we briefly elucidate the reciprocal regulation between HIF-1α and ncRNAs, as well as their effect on cancer cell behaviors. We also try to summarize the complex feedback loop existing between these two components. Moreover, we evaluated the biomarker potential of HRNs for the diagnosis and prognosis of cancer, as well as the potential clinical utility of shared regulatory mechanisms between HIF-1α and ncRNAs in cancer treatment, providing novel insights into tumorigenicity, which may lead to innovative clinical applications.
Highlights
Hypoxia is a common hallmark in the tumor microenvironment, and its occurrence originates from an imbalance in the supply and consumption of oxygen by rapidly growing tumors [1, 2]
Among the various transcription factors participating in the regulation of tumor cell fate, hypoxia-inducible factor-1 alpha (HIF-1α), the most important transcriptional regulator in response to hypoxia, has been robustly demonstrated to extensively modulate hypoxic gene expression and the signaling transduction networks related to the aforementioned adaptations [6, 7]
Continuing evidence indicates that both Hypoxia-inducible factor-1 alpha (HIF-1α) and noncoding RNAs (ncRNAs) play essential roles in human cancers
Summary
Hypoxia is a common hallmark in the tumor microenvironment, and its occurrence originates from an imbalance in the supply and consumption of oxygen by rapidly growing tumors [1, 2]. Puissegur et al described in detail that in A549 lung cancer cells, miR210 is upregulated by hypoxia-induced HIF-1α; afterward, increased miR-210 represses the electron transport chain via succinate dehydrogenase complex, subunit D (SDHD), and consequent accumulation of succinate inhibits PHD to stabilize HIF-1α, forming a positiveautoregulatory loop [167] Based on this feedback enhancement mechanism, the researchers later confirmed that this circular HIF-1α/miR-210 interaction decreases the mortality rate and promotes the radioresistant phenotype of non-small-cell lung carcinoma cell lines [168]. Confirmation of this mechanism in HeLa cells further exhibited its significance in cancer therapeutics [180] Based on this negative loop, in pancreatic cancer, HIF-1α-induced miR-646 expression was shown to target migration and invasion inhibitory protein (MIIP) to inhibit the deacetylation ability of HDAC6, which eventually promoted the acetylation and proteasomal degradation of HIF-1α [181]. Most ncRNA-targeted treatments remain in the early stages of development, future technical innovations will provide new opportunities, and better insights into the associations between HIF-1α and ncRNAs in cancer biology will lay wide theoretical foundations for ncRNArelated targeted therapies
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