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. 2019 Feb 20;10:125. doi: 10.3389/fgene.2019.00125

FIGURE 2.

FIGURE 2

The connection triangle. The miRNAs, hypoxia and the stem-like state all play a connected role that eventually culminates in the tumor aggressiveness. miRNAs and aggressiveness: miRNAs are often found dysregulated and have gain-of-function mutations in the miRNAs associated with the oncogenic property and loss-of-function mutations in the miRNAs with the tumor suppressor properties. miRNAs and stemness: miRNAs play a role in the regulation of cell self-renewal, differentiation and regulation of transcription factors including Nanog, SOX2 and OCT4 among others associated with the stem-like state. They also help the stem-like cells to override the G1/S checkpoint to sustain continual division. miRNAs and hypoxia: miRNAs assist forming hypoxic microenvironment and regulate the HIF switch during hypoxia. Switch of HIF-1 to HIF-2 and HIF-3 is required in order to adapt the cells to prolonged or chronic hypoxia that may otherwise lead to apoptosis. Hypoxia and aggressiveness: In intratumoral hypoxia, a phenomenon of the aggressive cancers, hypoxia inducible factor 1α (HIF-1α) is stabilized, and in turn, HIF-1 results in transcription of pro-survival target genes involved with tumor angiogenesis, invasion, cell survival, EMT, and metabolism among others. Hypoxic pseudopalisading zones are protected from chemoradiation because of vascular stasis and depletion of molecular oxygen cells contributing to aggressiveness. Hypoxia and miRNAs: under hypoxia, a group of miRNAs, hypoxia regulated miRNAs-HRMs, are deregulated modulating processes involved in tumor survival. Hypoxia and stemness: Hypoxia promotes reprogramming towards a cancer stem-like cell (CSC) phenotype and expansion of CSC populations, a population thought to be responsible for the maintenance and recurrence of the tumor. It is in the hypoxic regions also that the CSCs go into quiescence to escape from targeted therapy. Stemness and aggressiveness: It is believed that stem-like cells have the capacity to sustain tumorigenesis by maintaining the tumor growth. They also contribute to therapy resistance, invasion and metastasis. Stemness and miRNAs: Evidences have shown that stem-like cells fine tune the miRNA expression. This includes “inhibitory-like” role of the miRNAs associated with tumor differentiation to restore “stemness” a probable source for tumor recurrence.