High expression of HIF-2α and its anti-radiotherapy effect in lung cancer stem cells

Abstract

ABSTRACT. Hypoxia-inducible factor-2 alpha (HIF-2α) has been shown to regulate cell stemness, although the expression and effects of HIF-2α in lung cancer stem cells remained unclear. This study investigated HIF-2α expression in lung cancer stem cells, as well as the relationship between HIF-2α expression and radioresistance in lung cancer cells. Stem-like cells (CD133 + ) in the non-small-cell lung cancer cell line A549 were enriched by serum-free culture conditions, and CD133 + cells were sorted via fluorescence-activated cell sorting. A549 cells were treated with middle-infrared radiation, and the level of HIF-2α expression was determined by a quantitative polymerase chain reaction assay and western blot analysis. The level of HIF-2α expression in tissue sections from 50 cases of clinically confirmed non-small-cell lung cancer was determined via immunohistochemical analysis, and its correlation with prognosis after radiotherapy was analyzed. HIF-2α levels in CD133 + cells were significantly higher than those in CD133 -cells (P = 0.032). However, after radiation treatment, these levels were significantly upregulated in both CD133+ and CD133 -cells (P = 0.031 and P = 0.023, respectively). After irradiation, the proportions of apoptotic, dead, and autophagic CD133 + A549 cells were 18111 HIF-2α and radioresistance in lung cancer stem cells ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 18110-18120 (2015) considerably lower than those of CD133 -A549 cells (P < 0.05). Furthermore, the recovery of carcinoembryonic antigen to pre-radiation levels was more rapid in lung cancer patients with high levels of HIF-2α expression, and these patients had shorter survival times (P = 0.018). HIF-2α is highly expressed in lung cancer stem cells, which may lead to radioresistance. In conclusion, HIF-2α is a potential prognostic marker for lung cancer.

Cancer stem cells and hypoxia-inducible factors (Review)

“…In AML, HIF-1α is overexpressed and selectively activated in CD34 + CD38subsets (91). In lung cancer, hypoxia-induced CD133 expression is associated with the binding of OCT4 and SOX2 to the PROM1 promoter (92). The targeting of HIF-1α or HIF-2α by short hairpin RNA in CD133 + cells from a patient with glioblastoma inhibited their neurosphere-forming ability and proliferation, induced the caspase-dependent apoptotic effect in vitro and attenuated their tumor-initiating potential in vivo (93).…”

HIF-1α and HIF-2α Differently Regulate the Radiation Sensitivity of NSCLC Cells

“…Moreover, HIF-2α is highly expressed in cancer stem cells, which has been associated with a radioresistant phenotype in lung cancer. Consequently, HIF-2α negatively correlates with prognosis in patients treated with radiation [20].…”

LncRNA HIF2PUT inhibited osteosarcoma stem cells proliferation, migration and invasion by regulating HIF2 expression

“…LncRNA HIF2PUT (HIF-2a promoter upstream transcript), which is located at 2p21, on the antisense side of the promoter upstream region of a cancer-associated mRNA, hypoxia-inducible factor-2a (HIF-2a) was identified [6]. HIF-2a has previously been demonstrated to be associated with stem cell-like properties in stem cells, and in the cancer stem cells of numerous types of cancer [7][8][9]. Here, we investigated whether HIF2PUT (HIF-2a promoter upstream transcript) was related to osteosarcoma stem cells and the possible mechanism.…”