The HIF1α/HIF2α-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions

Abstract

Hypoxia-inducible factor 1α (HIF1α) promotes the malignant progression of glioblastoma under hypoxic conditions, leading to a poor prognosis for patients with glioblastoma; however, none of the therapies targeting HIF1α in glioblastoma have successfully eradicated the tumour. Therefore, we focused on the reason and found that treatments targeting HIF1α and HIF2α simultaneously increased tumour volume, but the combination of HIF1α/HIF2α-targeted therapies with temozolomide (TMZ) reduced tumourigenesis and significantly improved chemosensitization. Moreover, miR-210-3p induced HIF1α expression but inhibited HIF2α expression, suggesting that miR-210-3p regulates HIF1α/HIF2α expression. Epidermal growth factor (EGF) has been shown to upregulate HIF1α expression under hypoxic conditions. However, in the present study, in addition to the signalling pathways mentioned above, the upstream proteins HIF1α and HIF2α have been shown to induce EGF expression by binding to the sequences AGGCGTGG and GGGCGTGG. Briefly, in a hypoxic microenvironment the HIF1α/HIF2α-miR210-3p network promotes the malignant progression of glioblastoma through a positive feedback loop with EGF. Additionally, differentiated glioblastoma cells underwent dedifferentiation to produce glioma stem cells under hypoxic conditions, and simultaneous knockout of HIF1α and HIF2α inhibited cell cycle arrest but promoted proliferation with decreased stemness, promoting glioblastoma cell chemosensitization. In summary, both HIF1α and HIF2α regulate glioblastoma cell proliferation, dedifferentiation and chemoresistance through a specific pathway, which is important for glioblastoma treatments.

Identification of Key Functional Gene Signatures Indicative of Dedifferentiation in Papillary Thyroid Cancer

“…In recent years, many studies have explored undifferentiated thyroid cancer at pre-transcription, transcription, and translation levels, revealing that a considerable number of undifferentiated cancers develop from dedifferentiation of DTC. Studies have shown that dedifferentiation of colorectal cancer is closely related to TGF-β, Wnt, and Hedgehog signaling pathways ( 35 ), while dedifferentiation of glioblastoma is closely related to hypoxia ( 36 ). Our previous studies have also shown that metabolic pathways play an important role in dedifferentiation of thyroid cancer ( 13 ).…”

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

“…Interestingly, also specific miRNAs associated with HIF-1α up-regulation are involved in chemoresistance. For instance, the HIF-1α/mir-210 axis determines resistance to temozolomide in glioblastoma by increasing the cell proliferation and the acquisition of a stemness phenotype [ 134 ]. In keeping with these results, mir-210 is considered a biomarker predictive of chemoresistance in patients with metastatic breast cancer [ 135 ].…”

Targeting Drug Chemo-Resistance in Cancer Using Natural Products

“…Hypoxiainducible factor-1 is an oxygen-sensitive heterodimeric transcription factor composed of two subunits: α and β [217][218][219]. It was reported that chemoresistance is associated with a high level of HIF-1α expression in many cancer types including ovarian cancer, hepatocellular carcinoma, glioblastoma, and colorectal cancer [220][221][222][223]. Moreover, HIF-1α can trigger more than 60 genes involved in tumor growth, metastasis, cellular metabolism, the reduction of apoptosis, and poor prognosis [224,225].…”