Abstract 182: Smoking Carcinogen (BaP) enhances tumorigenic phenotypes of cervical cancer cells by modulation of HPV oncogenes and microRNA profiles
Authors: Zaman Mohd Saif , Chauhan Neeraj , Gara Rishi K. , Maher Diane , Kumari Sonam , Sikander Mohammed , Khan Sheema , Yallapu Murali M. , Jaggi Meena , Chauhan Subhash C. 
Published: August 2015

Cervical cancer (CxCa), one of the most common and deadly cancers among women worldwide, is associated with persistent Human Papillomavirus (HPV) infection. An importunate oncogenic HPV infection itself is not enough to immortalize and transform the epithelial host cell. Additional factors are needed to acquire an immortal, malignant and invasive phenotype. In addition to HPV infection, cigarette smoking is a known risk factor. Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, is among the numerous carcinogens associated with cigarette smoking. BaP levels have been found to be elevated in the cervical mucus of women who smoke. BaP has been shown to stimulate high levels of the viral oncoproteins E6 and E7 besides enhancing virion synthesis in cell lines prolifically infected with HPV. Furthermore, mixtures containing BaP, such as cigarette smoke condensate, have been shown to induce dramatic microRNA (miR) alterations in rodent lungs and in vitro human bronchial models. MiRs, small non-coding RNAs, regulate gene expression and their aberrant regulation/function has been reported in a large majority of cancers. Additionally, previous studies have shown the role of BaP in modulating miR profiles in different cancers. In this study we examine the effects of the carcinogen BaP on miRs and their related pathways in CxCa. In vitro treatment of CxCa cells with BaP resulted in an increase of expression of oncogenic miR-21 and decrease in tumor suppressor miR-214. MiR-21 has been shown to enhance chemoresistance to established regimens of chemotherapy and radiation therapy. In addition BaP also modulates the downstream pathways that these miRs regulate. BaP treatment increased the expression of oncogenic transcription factors such as NFkB-65, pSTAT-3, pSTAT-5 (transcription factors promoting miR-21 expression) and oncogenic cytokine IL-6, besides decreasing tumor suppressor PTEN (a target of miR-21). IL-6 is known to increase miR-21 expression through pSTAT-3 and pSTAT-5. Moreover, BaP in combination with IL-6 enhanced the migratory properties of CxCa cells. BaP also increased the nuclear translocation of β-catenin as observed through confocal microscopy. β-catenin is a direct target of miR-214. Natural or synthetic compounds that can mitigate BaP induced tumorigenic effects can have tremendous clinical significance. Herein, we report that curcumin (C) or its PLGA (poly [lactic-co-glycolic acid]) based nanoformulation (NC) effectively suppresses BaP induced tumorigenicity, regulates the expression of miRs and nuclear translocation of β-catenin associated with BaP in Caski/SiHa CxCa cells. In vivo experiments show that C/NC efficaciously reduced the tumor burden in xenograft mouse model. These data suggest a potential role of smoking in CxCa progression via regulating miR profiles and C/NC may effectively attenuate smoking induced CxCa progression.

Citation Format: Mohd Saif Zaman, Neeraj Chauhan, Rishi K. Gara, Diane Maher, Sonam Kumari, Mohammed Sikander, Sheema Khan, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Smoking Carcinogen (BaP) enhances tumorigenic phenotypes of cervical cancer cells by modulation of HPV oncogenes and microRNA profiles. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 182. doi:10.1158/1538-7445.AM2015-182