Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

Yang, Xiaoyu; Yin, Hubin; Zhang, Yunzhi; Li, Xinyuan; Tong, Hang; Zeng, Yizhou; Wang, Quan; He, Weiyang

doi:10.3892/ijo.2018.4376

Cited by 48 publications

(49 citation statements)

References 45 publications

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“…Hypoxia was found to inhibit cisplatin‐induced apoptosis in ovarian cancer cells and enhance chemoresistance to cisplatin . In bladder cancer cells, hypoxia was found to activate autophagy and significantly reduce gemcitabine‐induced apoptosis compared with normoxic conditions . In agreement with our findings, gemcitabine cytotoxicity was increased in bladder cancer cells when combined with the autophagy inhibitor 3‐MA.…”

Section: Discussionsupporting

confidence: 91%

PTBP3 promotes malignancy and hypoxia‐induced chemoresistance in pancreatic cancer cells by ATG12 up‐regulation

Weng

Jia

et al. 2020

J Cellular Molecular Medi

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Pancreatic ductal adenocarcinoma (PDAC) tumours exhibit a high level of heterogeneity which is associated with hypoxia and strong resistance to chemotherapy. The RNA splicing protein polypyrimidine tract‐binding protein 3 (PTBP3) regulates hypoxic gene expression by selectively binding to hypoxia‐regulated transcripts. We have investigated the role of PTBP3 in tumour development and chemotherapeutic resistance in human PDAC tissues and pancreatic cancer cells. In addition, we determined the sensitivity of cancer cells to gemcitabine with differential levels of PTBP3 and whether autophagy and hypoxia affect gemcitabine resistance in vitro. PTBP3 expression was higher in human pancreatic cancer than in paired adjacent tissues. PTBP3 overexpression promoted PDAC proliferation in vitro and tumour growth in vivo, whereas PTBP3 depletion had opposing effects. Hypoxia significantly increased the expression of PTBP3 in pancreatic cancer cells in vitro. Under hypoxic conditions, cells were more resistance to gemcitabine. Knockdown of PTBP3 results in decreased resistance to gemcitabine, which was attributed to attenuated autophagy. We propose that PTBP3 binds to multiple sites in the 3′‐UTR of ATG12 resulting in overexpression. PTBP3 increases cancer cell proliferation and autophagic flux in response to hypoxic stress, which contributes to gemcitabine resistance.

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Section: Discussionsupporting

confidence: 91%

PTBP3 promotes malignancy and hypoxia‐induced chemoresistance in pancreatic cancer cells by ATG12 up‐regulation

Weng

Jia

et al. 2020

J Cellular Molecular Medi

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“…Recent studies have reported that UVRAG not only promotes Beclin‐1‐mediated autophagy, but it also facilitates endosome/autophagosome maturation . Activation of autophagy can increase chemo‐ and radiotherapy resistance in bladder cancer . We also found that high expression of UVRAG predicted poor prognosis, which was consistent with the role of circUVRAG.…”

Section: Discussionsupporting

confidence: 86%

“…18,19 Activation of autophagy can increase chemo-and radiotherapy resistance in bladder cancer. [20][21][22] We also found that high expression of UVRAG predicted poor prognosis, which was consistent with the role of circUVRAG.…”

Section: Discussionsupporting

confidence: 85%

Silencing circular RNA UVRAG inhibits bladder cancer growth and metastasis by targeting the microRNA‐223/fibroblast growth factor receptor 2 axis

Yang

et al. 2018

Cancer Science

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Circular RNA UVRAG (circUVRAG), a type of non‐coding RNA, is derived and cyclized by part of the exon from the UVRAG gene. However, the role of circUVRAG in bladder cancer (BLCA) has not been reported. The purpose of the present study was therefore to characterize the role of circUVRAG in BLCA. Bioinformatics analysis showed interactive relationships among circUVRAG, microRNA‐223 (miR‐223), and fibroblast growth factor receptor 2 (FGFR2). Quantitative real‐time PCR was used to detect the expression of circUVRAG in BLCA cell lines. UM‐UC‐3 cells were stably transfected with siRNA against circUVRAG, and cell proliferation and migration ability were tested using the CCK8 assay, clone formation, and Transwell assays in vitro. Tumor xenograft formation and metastasis were determined using nude mice. Fluorescence in situ hybridization was used to confirm the subcellular localization of circUVRAG, and the luciferase reporter assay was used to confirm the relationships among circUVRAG, miR‐223, and FGFR2. Results showed that circUVRAG was upregulated in BLCA cell lines. Downregulation of circUVRAG expression suppressed proliferation and metastasis both in vitro and in vivo. Downregulation of circUVRAG suppressed FGFR2 expression by “sponging” miR‐223, which was confirmed by rescue experiments and luciferase reporter assay. Overall, the results showed that downregulation of circUVRAG suppressed the aggressive biological phenotype of BLCA. Taken together, silencing circular RNA UVRAG inhibited bladder cancer growth and metastasis by targeting the miR‐223/FGFR2 axis, which may provide a potential biomarker and therapeutic target for the management of BLCA.

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“…Autophagy, which is a mechanism of cellular degradation through lysosomes, is also involved in a HIF-1α-mediated cell survival mechanism (8,9). Hypoxia-induced autophagy can lead to chemoresistance and malignant progression of cancer cells (10). Therefore, suppression of hypoxia-induced autophagy may help inhibit the tumorigenesis of glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

The HIF‑1α/miR‑224‑3p/ATG5 axis affects cell mobility and chemosensitivity by regulating hypoxia‑induced protective autophagy in glioblastoma and astrocytoma

et al. 2018

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Human glioblastoma is a malignant and aggressive primary human brain solid tumor characterized by severe hypoxia. Hypoxia can induce autophagy, which may result in chemoresistance and malignant progression of cancer cells. MicroRNAs (miRNAs) have been reported to modulate hypoxia-induced autophagy in various types of cancers. In the present study, we observed that hypoxia-inducible factor (HIF)-1α expression was increased while miR-224-3p expression was decreased under hypoxia in a time-dependent manner in glioma LN229 and astrocytoma U-251MG cell lines, as deteced by western blot analysis and real-time quantitative polymerase chain reaction. In addition, HIF-1α knockout inhibited cell motility and chemosensitivity by negatively regulating the expression of miR-224-3p under a hypoxic condition by Transwell and MTT assay. Moreover, hypoxia increased the relative expression of ATG5 (autophagy-related gene 5) and LC3 II/I with a decreased level of p62. These results were correlated with autophagy in a time-dependent manner, suggesting that hypoxia induced autophagy in glioblastoma and astrocytoma cells. Through bioinformatic prediction and luciferase reporter assay, we confirmed that ATG5 is a target of miR-224-3p and ATG5 expression was negatively regulated by miR-224-3p. Knockdown of ATG5 inhibited cell mobility with increased chemosensitivity of glioblastoma cells under hypoxia. Moreover, overexpression of miR-224-3p also inhibited cell mobility with increased chemosensitivity of glioblastoma cells under hypoxia. However, activation of autophagy was able to counteract these effects of miR-224-3p. Furthermore, in vivo experiments indicated that the miR-224-3p mimic enhanced the chemosensitivity of LN229 cells to temozolomide by immunohistochemistry and TUNEL assay. In summary, our experiments elucidated that the HIF-1α/miR-224-3p/ATG5 axis affects cell mobility and chemosensitivity by regulating hypoxia-induced autophagy in glioblastoma and astrocytoma. Therefore, miR-224-3p could be a novel target against hypoxia-induced autophagy in glioblastoma and astrocytoma.

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Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

Cited by 48 publications

References 45 publications

PTBP3 promotes malignancy and hypoxia‐induced chemoresistance in pancreatic cancer cells by ATG12 up‐regulation

PTBP3 promotes malignancy and hypoxia‐induced chemoresistance in pancreatic cancer cells by ATG12 up‐regulation

Silencing circular RNA UVRAG inhibits bladder cancer growth and metastasis by targeting the microRNA‐223/fibroblast growth factor receptor 2 axis

The HIF‑1α/miR‑224‑3p/ATG5 axis affects cell mobility and chemosensitivity by regulating hypoxia‑induced protective autophagy in glioblastoma and astrocytoma

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