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Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma
- Source :
- Cellular Oncology. 44:1167-1181
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- Chemotherapy based on cisplatin (CDDP) has been established as the treatment of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironmental alterations through a dynamic balance between mitochondrial fission and fusion. HNSCCs are known to exhibit hypoxic conditions, yet the respective effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain to be resolved. The effect of hypoxia on the chemosensitivity of HNCC cells was determined by flow cytometry. Mitochondrial fission factor (Mff) expression was assessed by RT-PCR and Western blotting in hypoxic HNSCC cells, and further verified in primary CDDP-sensitive and CDDP-resistant HSNCC samples. The biological function of Mff was evaluated by loss of function and gain of function analyses, both in vitro and in vivo. We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was found to be correlated with chemosensitivity in primary clinical samples under hypoxic conditions. Hypoxia-inducible factor 1α (HIF-1α) was found to markedly increase Mff transcription and to directly bind to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α expression, Mff expression and mitochondrial fission. Moreover, Mff knockdown led to suppression of hypoxia-induced mitochondrial fission and to decreased CDDP chemosensitivity in vivo and in vitro. Our findings indicate that hypoxia-induced release of ROS can promote mitochondrial fission and CDDP chemosensitivity via HIF1α/Mff regulation in HNSCC cells, indicating that Mff may serve as a biomarker to predict neoadjuvant chemosensitivity in HNSCC patients and as a target for overcoming chemoresistance.
- Subjects :
- Cancer Research
Mitochondrial fission factor
Cell Survival
Mice, Nude
Antineoplastic Agents
Mitochondrial Dynamics
Flow cytometry
Mitochondrial Proteins
Downregulation and upregulation
Cell Line, Tumor
medicine
Animals
Humans
Hypoxia
neoplasms
Cisplatin
Mice, Inbred BALB C
Gene knockdown
medicine.diagnostic_test
Chemistry
Membrane Proteins
General Medicine
Hypoxia (medical)
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
Xenograft Model Antitumor Assays
Head and neck squamous-cell carcinoma
Gene Expression Regulation, Neoplastic
HEK293 Cells
Oncology
Head and Neck Neoplasms
Carcinoma, Squamous Cell
Cancer research
Tumor Hypoxia
Molecular Medicine
RNA Interference
Mitochondrial fission
medicine.symptom
Reactive Oxygen Species
medicine.drug
Subjects
Details
- ISSN :
- 22113436 and 22113428
- Volume :
- 44
- Database :
- OpenAIRE
- Journal :
- Cellular Oncology
- Accession number :
- edsair.doi.dedup.....9ae334a5b039b0c612dfa1bf3802b160
- Full Text :
- https://doi.org/10.1007/s13402-021-00629-6