PERAN GENOTIPE HUMAN PAPILLOMAVIRUS TERHADAP EKSPRESI MRNA C-MYC MELALUI STAT3, BETA-CATENIN, DAN NOTCH1 PADA KARSINOMA SEL SKUAMOSA ORAL MAN

ISADORA GRACIA , Dr. dr. Irianiwati, Sp.PA(K).; dr. Totok Utoro, D.Med.Sc., Sp.PA(K).; drg. Supriatno, M.Kes., MDSc., Ph.D

2018 | Disertasi | DOKTOR ILMU KEDOKTERAN DAN KESEHATAN

Latar belakang: Perubahan aktivitas c-Myc pada karsinoma sel skuamosa oral (KSSO) terkait Human papillomavirus (HPV) telah dilaporkan. Beberapa komponen bertindak sebagai regulator c-Myc seperti STAT3, beta-catenin, dan Notch1. Peran ketiga komponen tersebut terhadap HPV dan mRNA c-Myc pada KSSO belum banyak dilaporkan. Tujuan: Mengkaji pengaruh STAT3, beta-catenin, dan Notch1 terhadap hubungan HPV dan mRNA cMyc pada KSSO. Metode: Studi dengan desain cross-sectional dilakukan menggunakan 64 blok parafin lesi KSSO. Skrining genotipe kit digunakan untuk pemeriksaan HPV. Ekspresi mRNA dideteksi menggunakan qRT-PCR. Analisis statistik bivariat dilakukan untuk mengevaluasi perbedaan ekspresi mRNA antara kelompok HPV - positif dan HPV-negatif. Analisis Structural Equation Model dilakukan dalam evaluasi efek STAT3, beta-catenin, dan Notch1 pada hubungan HPV dan c-Myc. Hasil: DNA HPV terdeteksi pada 35 sampel (54,69%). Hasil genotyping adalah 3 sampel HPV-16 (8,57%), 8 sampel HPV-18 (22,86%), 14 sampel undetermined genotype (37,5%). mRNA c-Myc dan STAT3 kelompok HPV-positif lebih tinggi dibandingkan HPV-negatif (c-Myc: 124,90 fold; STAT3: 11,01 fold; p<0,05). mRNA beta-catenin dan Notch1 kelompok HPV-positif lebih tinggi dibandingkan HPV-negatif (beta-catenin: 1,06 fold, Notch1: 1,83 fold; p=0,05). Pada KSSO berdiferensiasi baik, pengaruh signifikan terhadap HPV dan c-Myc hanya ditunjukkan oleh STAT3. Pengaruh signifikan HPV terhadap c-Myc, beta-catenin, Notch1 tidak terdeteksi pada KSSO berdiferensiasi sedang-buruk. Kesimpulan: HPV mempengaruhi c-Myc, STAT3, beta-catenin, dan Notch1 pada KSSO. Pengaruh STAT3 terhadap HPV dan c-Myc lebih dominan dibandingkan beta-catenin dan Notch1 pada KSSO berdiferensiasi baik. Peran HPV minimal terhadap ekspresi komponen-komponen ini terlihat pada KSSO berdiferensiasi sedang-buruk.

Introduction: The aberrant c-Myc activity in Human papillomavirus (HPV) positive oral squamous cell carcinoma (OSCC) is well documented. Some components act as c-Myc regulators include STAT3, beta-catenin, and Notch1. The effect of these components on HPV and c-Myc has not been widely reported. Objective: The effect of STAT3, beta-catenin, and Notch1 on HPV and c-Myc mRNA relation was investigated. Methods: A cross-sectional study was performed using 64 paraffin blocks of OSCC lesions. HPV genotyping was carried out using a screening kit. Evaluation of mRNA expressions was conducted with qRT-PCR. Bivariate statistical analyzes were performed to evaluate differences in mRNA expression between HPV-positive and HPV-negative groups. The effect of STAT3, beta-catenin, and Notch1 on HPV and c-Myc mRNA was analyzed with Structural Equation Model. Results: HPV DNA detected in 35 samples (54.69%). Genotyping results were 3 HPV-16 (8.57%) samples, 8 HPV-18 samples (22.86%), 14 undetermined genotype samples (37.5%). c-Myc and STAT3 mRNA HPV-positive group were higher than HPV-negative (c-Myc: 124,90 fold; STAT3: 11,01 fold; p<0.05). beta- catenin and Notch1 mRNA HPV-positive groups were higher than HPV-negative (beta-catenin: 1.06 fold, Notch1: 1.83 fold; p-0,05). In well-differentiated OSCC, significant effects on HPV and c-Myc were showed only by STAT3. Significant effects of HPV on c-Myc, beta-catenin, Notch1 were not detected in moderately- poorly differentiated OSCC. Conclusion: HPV affected c-Myc, STAT3, beta-catenin, and Notch1 in OSCC. STAT3 showed dominant effect on HPV and c-Myc than beta-catenin and Notch1 in well-differentiated OSCC. The minimal HPV role on these components was showed in moderate-poorly differentiated OSCC.

Kata Kunci : HPV, mRNA c-Myc, STAT3, beta-catenin, Notch1, KSSO