Cross-Talk Between Hypoxia-Inducible Factors in Driving the Pathology of Oral Squamous Cell Carcinoma: An Immunohistochemical Analysis of the Role of Hypoxia-Inducible Factors and Cancer-Associated Fibroblasts

M, Indu; VT, Beena; Banerjee, Moinak; Cherian, Latha Mary; P, Aishwarya Menon; PS, Sajitha

doi:10.31557/APJCP.2025.26.8.3027

Cross-Talk Between Hypoxia-Inducible Factors in Driving the Pathology of Oral Squamous Cell Carcinoma: An Immunohistochemical Analysis of the Role of Hypoxia-Inducible Factors and Cancer-Associated Fibroblasts

Document Type : Research Articles

Authors

¹ Department of Oral Pathology, Govt Dental College Thrissur, Kerala, India.

² Directorate of Medical Education, Thiruvananthapuram, Kerala, India.

³ Human Molecular Genetics Laboratory, Rajiv Gandhi Centre for Biotechnology (RGCB), Thycaud Post, Poojappura, Thiruvananthapuram, Kerala 695014. India.

⁴ Department of Oral Pathology, Govt Dental College Kottayam, Kerala, India.

⁵ Consultant Oral Pathologist, Kerala, India.

⁶ Department of Public Health Dentistry, Government Dental College, Kozhikode, Kerala, India.

10.31557/APJCP.2025.26.8.3027

Abstract

Background: Tumor hypoxia refers to reduced oxygen levels in tumor tissues, and the transcription factors of cellular response to hypoxia are hypoxia-inducible factors (HIFs). Although the altered expression of HIFs has been identified in many malignancies, their role in oral squamous cell carcinoma (OSCC) is still debatable. Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment; however, the effects of hypoxia on CAFs require further investigation. Objectives: This observational study aimed to evaluate the HIF -1α and HIF - 2α expression in OSCC compared to normal oral mucosal tissues (NOM) using immunohistochemistry. Further, the study aimed to analyze the association of 1α and 2α isotypes of HIF with the clinicopathologic features of OSCC and their relationship with CAFs in tumor tissues. Materials and Methods: Immunostaining of HIF -1α and HIF - 2α, and alpha-smooth muscle actin (α- SMA; as a marker for CAFs) was performed on 50 OSCC and 50 NOM samples. Analysis of variance, chi-square test, and Mann–Whitney U test were used to analyze the data. A P value < 0.05 was considered significant. Results: HIF -1α and HIF - 2α, and α-SMA expressions were significantly higher in OSCC samples than in NOM (P < 0.001). The expressions of HIF-1α and HIF-2α were higher in histologically more differentiated tumor cells; however, the association with histologic grading was not significant. α-SMA exhibited a positive correlation with the expression of 1α and 2α isotypes of HIF. Conclusions: The elevated nuclear and stromal immunostaining of HIFs in OSCC substantiates their role in the pathogenesis of OSCC. The correlation between HIFs and α-SMA indicates an influence of hypoxia in inducing CAFs in oral cancer.

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