Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer
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(2020) 39:110
REVIEW
Open Access
Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer Antonietta Rosella Farina, Lucia Cappabianca, Michela Sebastiano, Veronica Zelli, Stefano Guadagni and Andrew Reay Mackay*
Abstract Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic reprogramming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease. The impressive number of hypoxia-induced alternative spliced protein isoforms that characterize tumour progression, classifies hypoxia-induced alternative splicing as the 11th hallmark of cancer, and offers a fertile source of potential diagnostic/prognostic markers and therapeutic targets. Keywords: Hypoxia, Alternative splicing, Cancer hallmarks
Background Tumour chemical and cellular microenvironments interact continually to select survival-adapted tumour cell and tumour-associated normal cell populations, and underpins both metastatic progression and therapeutic resistance. The tumour cellular microenvironment is comprised of “normal” (vascular, stromal and inflammatory cells) and neoplastic components that co-exist within a poorly defined and poorly organized extracellular matrix, characterized by heterogeneous niches created by a highly abnormal vasculature and episodes of microenvironmental hypoxic, nutrient, metabolic and redox stress, which elicit cellular hypoxic, nutrient, oxidative and metabolic stress responses. Tumour hypoxia
promotes glycolytic metabolic adaptation by tumour cellular components, combined with oncogene-promoted metabolic changes, result in the malignant tumourassociated “Warburg” metabo-type [1–3]. The metabotype, furthermore, promotes an acidic reducing tumour microenvironment, which together with tumour hypoxia, acts as potent driving forces for survival adaptation [4, 5], selecting “normal” and neoplastic tumour cellular components that exhibit increased resistance to programmed cell-death, a pro-angiogenic phenotype, sustained metabolic glycolytic reprogramming, progressive epithelial/mesenchymal (EMT) and stem cell-like dedifferentiation, enhanced motile, invas
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