Correlation between HPV PCNA, p16, and p21 Expression in Lung Cancer Patients

Abstract

Purpose. Evaluate if human papillomavirus (HPV) infection in lung cancer patients might be helping cancer development by altering p16, p21, and PCNA, key human genes involved in cell proliferation and tumor development. Methods. 63 fresh-frozen (FF) and formalin-fixed paraffin-embedded (FFPE) samples from lung tumor patients were used to detect HPV by PCR, followed by genotype through sequencing. The host gene expressions of p21, p16, and PCNA were quantified by qPCR in both FF and FFPE samples, and the expression of viral oncogenes E5, E6, and E7 was also measured by qPCR in 19 FF samples. Results. 74.6% of samples were positive for HPV, 33/44 FFPE samples and 14/19 FF samples. HPV-16 and HPV-18 were detected in 31/33 and 7/33 FFPE, respectively, and HPV-16 was the only type in FF samples. E5, E6, and E7 were expressed in 10/19, 2/19, and 4/19 FF samples, respectively. The p16 RNAm expression was higher in FF HPV+ samples and FFPE+FF HPV+ samples, while p21 showed higher expression in all HPV- samples. In turn, the PCNA expression was higher in HPV+ FF samples; however, in FFPE and FFPE+FF samples, PCNA was higher in HPV- samples. In FF samples, PCNA, p16, and p21 showed a significant positive correlation as well as E5 and E7, and E5 was inversely correlated to p21. In FFPE, also, a positive correlation was observed between PCNA HPV+ and p21 HPV+ and PCNA HPV+ and p16 HPV. In FF+FFPE analysis, a direct correlation was found between PCNA HPV+ and p21 HPV+, p21 HPV+ and p16 HPV+, and PCNA HPV- and p16 HPV-, and an inverse correlation between PCNA HPV+ and p16 HPV+. Also, the p16 protein was positive in 10 HPV+ samples and 1 HPV-. Conclusions. Our data show that lung cancer patients from Northeast Brazil have a high prevalence of HPV, and the virus also expresses its oncogenes and correlates with key human genes involved in tumor development. This data could instigate the development of studies focused on preventive strategies, such as vaccination, used as a prognostic indicator and/or individualized therapy.

Human Papillomavirus Is Rare and Does Not Correlate with p16INK4A Expression in Non-Small-Cell Lung Cancer in a Jordanian Subpopulation

“…On the contrary, Robinson et al investigated 70 NSCLC cases where p16 INK4a expression significantly correlated with the presence of HPV [53]. Further, high p16 INK4a expression may have provided more persuasive evidence that the virus has molecularly affected cellular proliferation, according to some studies [53,54].…”

“…HPV is a DNA virus that belongs to the Papovaviridae family and is genotyped into three groups based on its oncogenic risk: high-risk group (HR-HPV) such as HPVs 16,18,31,33,35,39,45,51,and 52, which can lead to cancerous transformation, probable/possible carcinogen such as HPVs 26, 53, 66, 68, 73, and 82, and low-risk-group (LR-HPV) such as HPVs 6,11,40,42,43,44,54,61, and 72, which cause benign lesions [8]. The HPV DNA encodes for several proteins, including the early (E) E1-E2, E4-E7, and late (L), L1, and L2 proteins, that carry oncogenic potential [9].…”

Advancing Immunotherapies for HPV-Related Cancers: Exploring Novel Vaccine Strategies and the Influence of Tumor Microenvironment

“…The detection of HPV DNA has been repeatedly reported in lung tumors worldwide [ 33 , 34 , 35 , 36 ], and while the association between infection and tumor progression is unclear, a recent study developed by Wang and collaborators investigated the possible interference of oncoproteins E5, E6, and E7 of HPV-16 transfected in H292 cells in the expression of the nuclear epidermal growth factor receptor (EGFR), where higher levels of EGFR were associated with greater sensitivity to cisplatin, a chemotherapeutic widely used to treat cancers [ 37 ].…”