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09-06-2024 | Oral Cancer | Original Article

The miR-199a-5p/HIF1α dual-regulatory axis participates in hypoxia-induced aggressive phenotypes of oral squamous cell carcinoma (OSCC) cells

Authors: Xing Chen, Jianjun Yu, Hao Tian, Xu Cai

Published in: International Journal of Clinical Oncology

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Abstract

Background

The late-stage diagnosis and distant metastasis of oral squamous cell carcinoma (OSCC) remain a huge challenge to clinical treatment for OSCC. During the past decades, targeting glycolysis-inducing factors becomes an attractive new strategy in OSCC therapies.

Methods

OSCC cells were stimulated with hypoxia or transfected with agomir-199a-5p, antagomir-199a-5p, and siRNA for HIF1A, cell proliferation was detected by CCK-8 assay; HIF1α, GLUT1, HK2 and LDHA expression levels were examined with western blot; miR-199 expression was determined with RT-PCR; cell migratory and invasive abilities were examined using wound healing and transwell assays; the lactate and glucose in culture medium were also determined. Luciferase assay or CHIP assay was applied for confirm the binding between miR-199a-5p and HIF1A 3′UTR, or between HIF1α and miR-199a promoter.

Results

HIF1α showed to be abnormally up-regulated, and miR-199a-5p showed to be abnormally down-regulated within OSCC under hypoxia. Hypoxia considerably enhanced OSCC cell proliferation, glycolysis, migratory ability, and invasive ability. MiR-199a-5p bound to HIF1A 3′‐UTR and suppressed HIF1A expression; HIF1α targeted miR-199a-5p promoter region and downregulated miR-199a-5p expression. Under hypoxia, miR-199a-5p overexpression significantly repressed HIF1α up-regulation inresponse to hypoxia, OSCC cell proliferation, glycolysis, migratory ability, and invasive ability.

Conclusion

miR-199a-5p and HIF1α form a dual-regulatory axis in OSCC cells; the miR-199a-5p/HIF1α dual-regulatory axis contributes to hypoxia-induced aggressive OSCC phenotypes.
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Literature
1.
go back to reference Warnakulasuriya S (2009) Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 45(4–5):309–316CrossRefPubMed Warnakulasuriya S (2009) Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 45(4–5):309–316CrossRefPubMed
2.
go back to reference Pulte D, Brenner H (2010) Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. Oncologist 15(9):994–1001CrossRefPubMedPubMedCentral Pulte D, Brenner H (2010) Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. Oncologist 15(9):994–1001CrossRefPubMedPubMedCentral
3.
4.
go back to reference Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277(26):23111–23115CrossRefPubMed Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277(26):23111–23115CrossRefPubMed
5.
go back to reference Chang CC et al (2011) HDAC2 promotes cell migration/invasion abilities through HIF-1alpha stabilization in human oral squamous cell carcinoma. J Oral Pathol Med 40(7):567–575CrossRefPubMed Chang CC et al (2011) HDAC2 promotes cell migration/invasion abilities through HIF-1alpha stabilization in human oral squamous cell carcinoma. J Oral Pathol Med 40(7):567–575CrossRefPubMed
6.
go back to reference Eckert AW et al (2011) Coexpression of hypoxia-inducible factor-1alpha and glucose transporter-1 is associated with poor prognosis in oral squamous cell carcinoma patients. Histopathology 58(7):1136–1147CrossRefPubMed Eckert AW et al (2011) Coexpression of hypoxia-inducible factor-1alpha and glucose transporter-1 is associated with poor prognosis in oral squamous cell carcinoma patients. Histopathology 58(7):1136–1147CrossRefPubMed
7.
go back to reference Mohamed KM et al (2004) Correlation between VEGF and HIF-1alpha expression in human oral squamous cell carcinoma. Exp Mol Pathol 76(2):143–152CrossRefPubMed Mohamed KM et al (2004) Correlation between VEGF and HIF-1alpha expression in human oral squamous cell carcinoma. Exp Mol Pathol 76(2):143–152CrossRefPubMed
8.
go back to reference Guo M et al (2018) Comparison of the expression of TGF-beta1, E-cadherin, N-cadherin, TP53, RB1CC1 and HIF-1alpha in oral squamous cell carcinoma and lymph node metastases of humans and mice. Oncol Lett 15(2):1639–1645PubMed Guo M et al (2018) Comparison of the expression of TGF-beta1, E-cadherin, N-cadherin, TP53, RB1CC1 and HIF-1alpha in oral squamous cell carcinoma and lymph node metastases of humans and mice. Oncol Lett 15(2):1639–1645PubMed
9.
go back to reference Bartels CL, Tsongalis GJ (2009) MicroRNAs: novel biomarkers for human cancer. Clin Chem 55(4):623–631CrossRefPubMed Bartels CL, Tsongalis GJ (2009) MicroRNAs: novel biomarkers for human cancer. Clin Chem 55(4):623–631CrossRefPubMed
10.
go back to reference Cortes-Sempere M, Ibanez de Caceres I (2011) microRNAs as novel epigenetic biomarkers for human cancer. Clin Transl Oncol 13(6):357–362CrossRefPubMed Cortes-Sempere M, Ibanez de Caceres I (2011) microRNAs as novel epigenetic biomarkers for human cancer. Clin Transl Oncol 13(6):357–362CrossRefPubMed
12.
go back to reference Shin KH et al (2011) miR-181a shows tumor suppressive effect against oral squamous cell carcinoma cells by downregulating K-ras. Biochem Biophys Res Commun 404(4):896–902CrossRefPubMed Shin KH et al (2011) miR-181a shows tumor suppressive effect against oral squamous cell carcinoma cells by downregulating K-ras. Biochem Biophys Res Commun 404(4):896–902CrossRefPubMed
13.
go back to reference Jiang X et al (2020) CCL18-induced LINC00319 promotes proliferation and metastasis in oral squamous cell carcinoma via the miR-199a-5p/FZD4 axis. Cell Death Dis 11(9):777CrossRefPubMedPubMedCentral Jiang X et al (2020) CCL18-induced LINC00319 promotes proliferation and metastasis in oral squamous cell carcinoma via the miR-199a-5p/FZD4 axis. Cell Death Dis 11(9):777CrossRefPubMedPubMedCentral
14.
go back to reference Wei D et al (2019) MicroRNA199a5p suppresses migration and invasion in oral squamous cell carcinoma through inhibiting the EMTrelated transcription factor SOX4. Int J Mol Med 44(1):185–195PubMedPubMedCentral Wei D et al (2019) MicroRNA199a5p suppresses migration and invasion in oral squamous cell carcinoma through inhibiting the EMTrelated transcription factor SOX4. Int J Mol Med 44(1):185–195PubMedPubMedCentral
15.
go back to reference Lou Z et al (2018) Low expression of miR-199 in hepatocellular carcinoma contributes to tumor cell hyper-proliferation by negatively suppressing XBP1. Oncol Lett 16(5):6531–6539PubMedPubMedCentral Lou Z et al (2018) Low expression of miR-199 in hepatocellular carcinoma contributes to tumor cell hyper-proliferation by negatively suppressing XBP1. Oncol Lett 16(5):6531–6539PubMedPubMedCentral
16.
go back to reference Bu XN et al (2016) Inhibition of DACH1 activity by short hairpin RNA represses cell proliferation and tumor invasion in pancreatic cancer. Oncol Rep 36(2):745–754CrossRefPubMed Bu XN et al (2016) Inhibition of DACH1 activity by short hairpin RNA represses cell proliferation and tumor invasion in pancreatic cancer. Oncol Rep 36(2):745–754CrossRefPubMed
17.
go back to reference Li M et al (2022) MiR-26a-5p regulates proliferation, apoptosis, migration and invasion via inhibiting hydroxysteroid dehydrogenase like-2 in cervical cancer cell. BMC Cancer 22(1):876CrossRefPubMedPubMedCentral Li M et al (2022) MiR-26a-5p regulates proliferation, apoptosis, migration and invasion via inhibiting hydroxysteroid dehydrogenase like-2 in cervical cancer cell. BMC Cancer 22(1):876CrossRefPubMedPubMedCentral
18.
go back to reference Chang QQ et al (2019) LncRNA PVT1 promotes proliferation and invasion through enhancing Smad3 expression by sponging miR-140-5p in cervical cancer. Radiol Oncol 53(4):443–452CrossRefPubMedPubMedCentral Chang QQ et al (2019) LncRNA PVT1 promotes proliferation and invasion through enhancing Smad3 expression by sponging miR-140-5p in cervical cancer. Radiol Oncol 53(4):443–452CrossRefPubMedPubMedCentral
19.
20.
go back to reference Sasabe E et al (2010) Reactive oxygen species produced by the knockdown of manganese-superoxide dismutase up-regulate hypoxia-inducible factor-1alpha expression in oral squamous cell carcinoma cells. Free Radic Biol Med 48(10):1321–1329CrossRefPubMed Sasabe E et al (2010) Reactive oxygen species produced by the knockdown of manganese-superoxide dismutase up-regulate hypoxia-inducible factor-1alpha expression in oral squamous cell carcinoma cells. Free Radic Biol Med 48(10):1321–1329CrossRefPubMed
21.
go back to reference Chen H et al (2022) BMP9-ID1 signaling activates HIF-1α and VEGFA expression to promote tumor angiogenesis in hepatocellular carcinoma. Int J Mol Sci 23(3):1475CrossRefPubMedPubMedCentral Chen H et al (2022) BMP9-ID1 signaling activates HIF-1α and VEGFA expression to promote tumor angiogenesis in hepatocellular carcinoma. Int J Mol Sci 23(3):1475CrossRefPubMedPubMedCentral
22.
go back to reference Ma P et al (2021) GLUT1 targeting and hypoxia-activating polymer-drug conjugate-based micelle for tumor chemo-thermal therapy. Drug Delivery 28(1):2256–2267CrossRefPubMedPubMedCentral Ma P et al (2021) GLUT1 targeting and hypoxia-activating polymer-drug conjugate-based micelle for tumor chemo-thermal therapy. Drug Delivery 28(1):2256–2267CrossRefPubMedPubMedCentral
24.
go back to reference Baltaziak M et al (2013) The relationships between hypoxia-dependent markers: HIF-1alpha, EPO and EPOR in colorectal cancer. Folia Histochem Cytobiol 51(4):320–325CrossRefPubMed Baltaziak M et al (2013) The relationships between hypoxia-dependent markers: HIF-1alpha, EPO and EPOR in colorectal cancer. Folia Histochem Cytobiol 51(4):320–325CrossRefPubMed
25.
go back to reference Malekan M, Ebrahimzadeh MA, Sheida F (2021) The role of hypoxia-inducible factor-1alpha and its signaling in melanoma. Biomed Pharmacother 141:111873CrossRefPubMed Malekan M, Ebrahimzadeh MA, Sheida F (2021) The role of hypoxia-inducible factor-1alpha and its signaling in melanoma. Biomed Pharmacother 141:111873CrossRefPubMed
27.
go back to reference Blouw B et al (2003) The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4(2):133–146CrossRefPubMed Blouw B et al (2003) The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4(2):133–146CrossRefPubMed
28.
go back to reference Mack FA et al (2003) Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell 3(1):75–88CrossRefPubMedPubMedCentral Mack FA et al (2003) Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth. Cancer Cell 3(1):75–88CrossRefPubMedPubMedCentral
29.
go back to reference Velasco-Hernandez T et al (2014) HIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia. Blood 124(24):3597–3607CrossRefPubMed Velasco-Hernandez T et al (2014) HIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia. Blood 124(24):3597–3607CrossRefPubMed
30.
go back to reference Eckert AW et al (2010) HIF-1alpha is a prognostic marker in oral squamous cell carcinomas. Int J Biol Markers 25(2):87–92CrossRefPubMed Eckert AW et al (2010) HIF-1alpha is a prognostic marker in oral squamous cell carcinomas. Int J Biol Markers 25(2):87–92CrossRefPubMed
31.
go back to reference Tilakaratne WM, Nissanka-Jayasuriya EH (2011) Value of HIF-1alpha as an independent prognostic indicator in oral squamous cell carcinoma. Expert Rev Mol Diagn 11(2):145–147CrossRefPubMed Tilakaratne WM, Nissanka-Jayasuriya EH (2011) Value of HIF-1alpha as an independent prognostic indicator in oral squamous cell carcinoma. Expert Rev Mol Diagn 11(2):145–147CrossRefPubMed
32.
go back to reference Augustin R (2010) The protein family of glucose transport facilitators: it’s not only about glucose after all. IUBMB Life 62(5):315–333CrossRefPubMed Augustin R (2010) The protein family of glucose transport facilitators: it’s not only about glucose after all. IUBMB Life 62(5):315–333CrossRefPubMed
33.
go back to reference Mathupala SP, Ko YH, Pedersen PL (2009) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol 19(1):17–24CrossRefPubMed Mathupala SP, Ko YH, Pedersen PL (2009) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol 19(1):17–24CrossRefPubMed
35.
go back to reference Sun X et al (2014) Clinicopathological significance and prognostic value of lactate dehydrogenase A expression in gastric cancer patients. PLoS ONE 9(3):e91068CrossRefPubMedPubMedCentral Sun X et al (2014) Clinicopathological significance and prognostic value of lactate dehydrogenase A expression in gastric cancer patients. PLoS ONE 9(3):e91068CrossRefPubMedPubMedCentral
36.
go back to reference Wei D et al (2019) MicroRNA199a5p functions as a tumor suppressor in oral squamous cell carcinoma via targeting the IKKbeta/NFkappaB signaling pathway. Int J Mol Med 43(4):1585–1596PubMedPubMedCentral Wei D et al (2019) MicroRNA199a5p functions as a tumor suppressor in oral squamous cell carcinoma via targeting the IKKbeta/NFkappaB signaling pathway. Int J Mol Med 43(4):1585–1596PubMedPubMedCentral
37.
go back to reference Li L et al (2016) Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res 76(7):1770–1780CrossRefPubMed Li L et al (2016) Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res 76(7):1770–1780CrossRefPubMed
38.
go back to reference Martínez-Sáez O et al (2017) Targeting HIF-2 α in clear cell renal cell carcinoma: a promising therapeutic strategy. Crit Rev Oncol Hematol 111:117–123CrossRefPubMed Martínez-Sáez O et al (2017) Targeting HIF-2 α in clear cell renal cell carcinoma: a promising therapeutic strategy. Crit Rev Oncol Hematol 111:117–123CrossRefPubMed
39.
go back to reference Zhu S et al (2016) MiR-548an, transcriptionally downregulated by HIF1α/HDAC1, suppresses tumorigenesis of pancreatic cancer by targeting vimentin expression. Mol Cancer Ther 15(9):2209–2219CrossRefPubMed Zhu S et al (2016) MiR-548an, transcriptionally downregulated by HIF1α/HDAC1, suppresses tumorigenesis of pancreatic cancer by targeting vimentin expression. Mol Cancer Ther 15(9):2209–2219CrossRefPubMed
40.
go back to reference Reece KM et al (2014) Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1α/p300 complex in a preclinical model of prostate cancer. Mol Cancer 13:91CrossRefPubMedPubMedCentral Reece KM et al (2014) Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1α/p300 complex in a preclinical model of prostate cancer. Mol Cancer 13:91CrossRefPubMedPubMedCentral
Metadata
Title
The miR-199a-5p/HIF1α dual-regulatory axis participates in hypoxia-induced aggressive phenotypes of oral squamous cell carcinoma (OSCC) cells
Authors
Xing Chen
Jianjun Yu
Hao Tian
Xu Cai
Publication date
09-06-2024
Publisher
Springer Nature Singapore
Published in
International Journal of Clinical Oncology
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI
https://doi.org/10.1007/s10147-024-02555-7

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