Abstract
Lung cancer is one of the most common and lethal malignant tumors and the cases increased rapidly. Elevated chemoresistance during chemotherapy resistance remains a challenge. Hypoxia is one of the components that lead to chemoresistance. PVT1 participates in various tumor drug resistance and is associated with hypoxia conditions. The present study aimed to analyze the regulatory relationship of hypoxia and PVT1 and the mechanism of PVT1 in the hypoxia-induced chemoresistance process of lung cancer. The expression of PVT1 in lung cancer and adjacent tissues, and cell lines were analyzed using the TCGA database and qPCR. The regulatory relationship between hypoxia and PVT1 was validated and analyzed with qPCR, luciferase reporter system, and CHIP-qPCR. The role of PVT1 in chemoresistance ability induced by hypoxia was analyzed with CCK-8 assay and flow cytometry. The roles of PVT1, hypoxia, and chemoresistance were also analyzed with LC3-GFP transfection, WB, and IHC. Finally, the results were further validated in xenograft models. PVT1 is highly expressed in lung cancer and cell lines, and the expression of PVT1 is regulated by HIF-1α, and the luciferase reporter assay and CHIP-qPCR analysis indicated that HIF-1α could bind to the promoter region of PVT1 and regulate PVT1 expression. PVT1 participated in hypoxia-induced chemoresistance and induced higher viability and lower apoptosis rate by the autophagy signaling pathway via PVT1/miR-140-3p/ATG5 axis. All the findings were validated in the xenograft models. In conclusion, these results suggest that the expression of PVT1 is regulated by HIF-1α and participates in hypoxia-induced chemoresistance.
Highlights
Lung cancer is one of the most common types of malignant tumors
The hypoxia-induced Long noncoding RNA (lncRNA) such as UPK1A, UPK1A-AS1, and circAKT3 participate in the genesis of chemoresistance [36, 37]
Finding the hypoxia-related lncRNAs and analyzing the mechanism might be a way to find the therapeutic targets in the treatment of lung cancer
Summary
Lung cancer is one of the most common types of malignant tumors. According to the cancer epidemiological statistics data, almost 228,820 newly diagnosed cases and 135,720 cancer deaths appeared worldwide in 2020 [1]. The hypoxic environment leads to cancer cells proliferation, migration, chemoresistance, and immune escape by regulating hypoxiainducible factor (HIF)-1α-related genes and signaling pathways [7]. The autophagy signaling pathway plays a significant role in regulating cellular chemoresistance to cisplatin in lung cancer [14, 15]. Long noncoding RNA (lncRNA) is a kind of noncoding RNA that is>200 nt and participates in regulating various cellular progresses, such as proliferation, migration, and chemoresistance [17] The former researches demonstrated that PVT1 promoted cancer progression by promoting proliferation, migration, or inhibiting apoptosis in colon cancer, breast cancer, and pancreatic cancer [18–21]. Our results revealed a novel mechanism of Hypoxia regulates PVT1 expression via HIF-1α hypoxia-induced chemoresistance and suggested a promising We analyzed which factor induces PVT1 expression in lung treatment target for lung cancer.
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