HPV-induced carcinogenesis of the uterine cervix is associated with reduced serum ATRA level.

Abstract

OBJECTIVE: In uterine cervical cancer, certain oncogenic HPV types are considered as key etiologic factor. But the progression of HPV associated cervical precancerous lesions depends on many other factors such as oncogenes, immune system, anti-viral factors etc. This study is therefore focused on the effect of an important dietary anti-viral factor called All Trans Retinoic Acid (ATRA) on the development of HPV associated cervical cancer as it is found higher in poor socioeconomic people. METHOD: We analyzed a total population of 130 including control subjects who have no complaints of uterine cervical lesions and the HPV-6/11, 16/18 infected cases of low grade squamous intraepithelial lesions [SIL], high grade squamous intraepithelial lesions [HSIL], and invasive cancers, for serum ATRA level. This study also focused to find out the association of serum ATRA level with the proliferation status in terms of proliferating cell nuclear antigen (PCNA) expression as it is an anti-proliferation agent and with the grades of cervical lesions, using SPSS statistical package. RESULTS: The results showed a highly significant negative association for serum ATRA level with different stages of cervical lesions (F = 3.305; P = 0.000) by one-way ANOVA and with intensity of PCNA expression (r = -0.825; P < 0.01) by Pearson's correlation test. A highly significant association was observed for the PCNA expression with the grades of cervical lesions too (F = 37.89; P = 0.000). Further, we found from our data that all the invasive cancer cases were infected with HPV-16/18 and none with HPV-6/11. Hence, we analyzed the association of serum ATRA level with HPV-16/18 infected preinvasive cases in developing invasiveness, by Fisher's Exact Test, using Graph Pad Prism as shown in Table 1. The results show an odds ratio (OR) of 36.93 and a relative risk (RR) of 4.99 with an 95% interval being 2.896 to 8.603, which is significant at the level of P = 0.0001 for the reduced [<0.6 mug/ml] serum ATRA level in developing invasive cancer in HPV-16/18 infected preinvasive cases. CONCLUSION: All these results suggest that the serum ATRA level highly influences the progression of cervical lesions to invasive cancer and can be therefore aimed as a marker for progression in combination with HPV-16/18, which helps to enhance the modalities of therapy towards cost effectiveness.