Potential role of HIF-1-responsive microRNA210/HIF3 axis on gemcitabine resistance in cholangiocarcinoma cells

Silakit, Runglawan; Kitirat, Yingpinyapat; Thongchot, Suyanee; Loilome, Watcharin; Techasen, Anchalee; Ungarreevittaya, Piti; Khuntikeo, Narong; Yongvanit, Puangrat; Yang, Ji Hye; Kim, N. H.; Yook, Jong In; Namwat, Nisana

doi:10.1371/journal.pone.0199827

Cited by 27 publications

(20 citation statements)

References 50 publications

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“…Previous research reported that HIF-1α can regulate transcription of multiple miRNAs in hypoxia (29). The study by Silakit et al indicated that miR-210 acted as downstream of HIF-1α and was upregulated in various cancer cells under hypoxia condition (30). The research by Guo et al demonstrated that miR-224-3p was one of the downregulated miRNAs in glioblastoma cells under hypoxia (31).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Increased miR-210 expression in CCA tissues was shown, compared with normal bile duct tissues, and associated with shorter survival [ 26 ]. In a pseudohypoxia status induced by CoCl 2 treatment, miR-210 suppressed the proliferation of malignant cholangiocytes through increasing cell cycle arrest at G2/M phase [ 26 ]. Furthermore, miR-210 decreased gemcitabine sensitivity by targeting HIF-3α, a negative regulator of HIF-1α.…”

Section: Mirnas and Resistance To Gemcitabinementioning

confidence: 99%

“…Furthermore, miR-210 decreased gemcitabine sensitivity by targeting HIF-3α, a negative regulator of HIF-1α. Overall, Silakit et al demonstrated that the positive feedback loop of miR-210/HIF-1α, by regulating HIF-3α, may contribute to cell arrest and gemcitabine resistance of CCA under hypoxia [ 26 ].…”

Section: Mirnas and Resistance To Gemcitabinementioning

confidence: 99%

The Emerging Role of MicroRNAs in Regulating the Drug Response of Cholangiocarcinoma

Huang

Yeh

2020

Biomolecules

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Cholangiocarcinoma (CCA) is the most common biliary malignancy, and has a poor prognosis. The median overall survival with the standard-of-care chemotherapy (Gemcitabine and cisplatin) in patients with advanced-stage CCA is less than one year. The limited efficacy of chemotherapy or targeted therapy remains a major obstacle to improving survival. The mechanisms involved in drug resistance are complex. Research efforts focusing on the distinct molecular mechanisms underlying drug resistance should prompt the development of treatment strategies that overcome chemoresistance or targeted drug resistance. MicroRNAs (miRNAs) are a class of evolutionarily conserved, short noncoding RNAs regulating gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to participate in almost all CCA hallmarks, including cell proliferation, migration and invasion, apoptosis, and the epithelial-to-mesenchymal transition. Emerging evidence demonstrates that miRNAs play a role in regulating responses to chemotherapy and targeted therapy. Herein, we present an overview of the current knowledge on the miRNA-mediated regulatory mechanisms underlying drug resistance among CCA. We also discuss the application of miRNA-based therapeutics to CCA, providing the basis for innovative treatment approaches.

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“…MiR-210 is upregulated by hypoxia in most of solid tumors and targets genes involved in cell cycle regulation, cell survival, differentiation, angiogenesis, metabolism and cancer cell immune evasion [103]. This miRNA is considered a master hypox-amiR and a new biomarker of metastatic potential and chemoresistance in different solid tumors [104][105][106].…”

Section: Micrornasmentioning

confidence: 99%

Understanding the crosstalk of molecular factors and signaling pathways reveals novel biomarkers of cisplatin resistance in testicular germ cell tumors

Roška

Jurkovičová

2020

neo

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Testicular germ cell tumors (TGCTs) mostly affect young men, but fortunately belong to well curable solid tumors. Today, different treatment strategies are applied reaching excellent outcomes, and introduction of alternative approach of patient active surveillance or adjuvant chemotherapy after orchiectomy decreases number of unnecessary toxic treatments of young patients. Also for relapsing patients, salvage therapy offers high survival rates. However, small percentages of affected young men do not respond to conventional therapy regimen due to intrinsic or acquired therapy resistance. For closely watching of patients during active surveillance, patients' stratification due to their prognosis, detection of therapy resistance and early relapse before treatment initiation, reliable molecular biomarkers and diagnostic tools replacing conventional approaches are still needed. Complex understanding of disease development and progression as well as mechanisms of chemoresistance and their epigenetic or chronobiological regulation prerequisite successful search for such novel biomarkers. In this review, we aimed to highlight the importance of crosstalk of different regulatory mechanisms and their key players affecting treatment response, and focus on their potential as novel molecular biomarkers and/or druggable targets.

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Potential role of HIF-1-responsive microRNA210/HIF3 axis on gemcitabine resistance in cholangiocarcinoma cells

Cited by 27 publications

References 50 publications

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

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

The Emerging Role of MicroRNAs in Regulating the Drug Response of Cholangiocarcinoma

Understanding the crosstalk of molecular factors and signaling pathways reveals novel biomarkers of cisplatin resistance in testicular germ cell tumors

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