Oral Squamous Cell Carcinoma (OSCC) is one of the most common types of oral cancer originating from the squamous epithelium. Classic risk factors include smoking, alcohol consumption, and infection with the Human Papillomavirus (HPV). HPV, particularly high-risk genotypes such as HPV-16 and HPV-18, has long been known to play a role in various head and neck cancers, including OSCC. However, the molecular mechanisms by which HPV induces malignant transformation of epithelial cells continue to be actively investigated.
One study conducted by FKG UGM student Isadora Gracia under the supervision of Dr. dr. Irianiwati, Sp.PA(K), dr. Totok Utoro, D.Med.Sc., Sp.PA(K), and Prof. drg. Supriatno, M.Kes., MDSc., Ph.D., entitled “The Role of Human Papillomavirus Genotypes on c-MYC mRNA Expression through STAT3, Beta-Catenin, and Notch1 in Oral Squamous Cell Carcinoma”, examined how HPV genotypes influence the expression of key oncogenic genes in OSCC tissue.
Mechanisms Linking HPV and OSCC
HPV Infection and Cellular Transformation
HPV infects mucosal epithelial tissue, and part of its genetic material may integrate into the host cell DNA. In high-risk genotype infections, viral oncoproteins E6 and E7 can inactivate tumor suppressor proteins p53 and Rb. This leads to increased cell proliferation, impaired DNA repair mechanisms, and accumulation of mutations that promote carcinogenesis.
Activation of Oncogenic Pathways: c-MYC, STAT3, β-Catenin, and Notch1
The study found that in HPV-positive OSCC cases, the expression of c-MYC and STAT3 mRNA was significantly higher than in HPV-negative cases. c-MYC expression increased more than 120-fold, while STAT3 increased more than 10-fold. In addition, β-catenin and Notch1 were also upregulated in the HPV-positive group.
Analysis showed that STAT3 had the most dominant influence in the relationship between HPV infection and increased c-MYC expression, particularly in well-differentiated OSCC. In simplified terms, the mechanism can be described as follows:
HPV infection → STAT3 activation (along with β-catenin and Notch1) → increased c-MYC expression → abnormal epithelial cell proliferation → development of OSCC.
Research Evidence and Clinical Significance
The study demonstrated that more than half of the OSCC samples analyzed contained HPV DNA. The increased expression of c-MYC and STAT3 in HPV-positive cases indicates that HPV infection can activate oncogenic pathways that accelerate tumor growth and progression.
Interestingly, the effect of HPV on these regulatory genes was most evident in well-differentiated OSCC, while in moderately to poorly differentiated OSCC, the influence was not significant. This suggests that HPV status is not only a risk factor but may also serve as a determinant of tumor biological characteristics and therapeutic response.
Clinical Implications
Beberapa implikasi klinis dari hubungan HPV dengan KSSO antara lain:
- HPV detection as part of diagnosis – Assessing HPV status in OSCC patients may help predict prognosis and tumor aggressiveness.
- Molecular targeted therapy – The STAT3 and c-MYC pathways activated in HPV-positive cases may serve as potential therapeutic targets in oral cancer.
- Prevention through vaccination – High-risk HPV vaccination programs may help reduce the incidence of HPV-related oral cancers.
- Patient stratification – HPV-positive OSCC patients may require different therapeutic approaches and monitoring compared to HPV-negative patients.
Challenges and Future Research Directions
Further studies are needed to evaluate how HPV status and activation of STAT3, β-catenin, and Notch1 pathways influence long-term patient prognosis. Interventional studies are also required to test the effectiveness of inhibiting these molecular targets in oral cancer treatment. In addition, other risk factors such as smoking and alcohol consumption should be analyzed concurrently to achieve a more comprehensive understanding.
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HPV infection plays a significant role in the pathogenesis of Oral Squamous Cell Carcinoma. Through activation of molecular pathways such as STAT3, β-catenin, and Notch1, HPV can increase the expression of the oncogene c-MYC, accelerating epithelial cell proliferation and malignant transformation. Understanding this relationship opens opportunities for early detection, prevention through vaccination, and the development of new molecular targeted therapies for HPV-related oral cancer.
References
ISADORA GRACIA , Dr. dr. Irianiwati, Sp.PA(K).; dr. Totok Utoro, D.Med.Sc., Sp.PA(K).; Prof. drg. Supriatno, M.Kes., MDSc., Ph.D. , “PERAN GENOTIPE HUMAN PAPILLOMAVIRUS TERHADAP EKSPRESI MRNA C-MYC MELALUI STAT3, BETA-CATENIN, DAN NOTCH1 PADA KARSINOMA SEL SKUAMOSA ORAL MAN”, https://etd.repository.ugm.ac.id/penelitian/detail/163428
Author: Rizky B. Hendrawan | Photo: Freepik
