Cervical cancer (CC) is a significant health issue globally, ranking fourth in terms of both incidence and mortality worldwide. However, its impact in India is particularly pronounced, where it is the second most prevalent malignancy affecting women. Several factors contribute to the high burden of cervical cancer in India, including lower socioeconomic status, limited access to healthcare resources, and a high prevalence of human papillomavirus (HPV) infection (Sathishkumar et al., 2023). In India, cervical cancer contributes to approximately 6–29 % of all cancers in women (Bobdey et al., 2016). Persistent infection with high-risk human papillomavirus (HPV) is a critical factor in the genesis and development of cervical cancer. While HPV vaccines could be a preventive measure, in its metastatic state, cervical cancer is indeed considered incurable with current treatment options; this emphasizes the need for targeted therapy (Weinstein et al., 2013). It is a complex disease involving hundreds of pathways for the disease progression. It is obvious that studying all or many of these pathways simultaneously is experimentally quite challenging; hence the necessity for application of computational systems biology in cervical cancer research as a fast, reliable and holistic platform quite pertinent.

Here, we undertake a multi-pronged systems biology approach utilizing protein-protein interaction data to comprehend and identify functionally significant proteins in human cervical cancer. Differentially expressed genes identified from the transcriptomics data obtained from normal and cervical cancerous tissues mapped onto the protein-protein interaction network followed by mathematical model-based network analysis facilitated the identification of key network proteins that are likely to play crucial roles in cervical cancer development and progression.

Androgen receptor (AR) has emerged as a candidate target in cervical cancer through our network biology analyses. AR is part of the steroid receptor superfamily, which governs gene expression in a ligand-dependent manner. Typically found in the cytoplasm when devoid of androgens, AR relocates to the nucleus upon binding to its ligand 5α-dihydrotestosterone (DHT), to initiate gene expression. As a transcription factor, AR is involved in regulating the expression of genes that control a wide range of biological processes including cell proliferation, migration, and apoptosis. AR regulates the transcriptional activity and expression of downstream target genes by interacting with the coactivators or corepressors, as well as upstream or downstream regulators through classical or non-classical AR signaling pathways (Davey and Grossmann, 2016). Although AR is a well-established marker for prostate cancer, its role in gynecological cancers, specifically cervical cancer, remains largely unknown (Wu et al., 2022). There are only a couple of studies that have shown downregulation of AR in cervical cancer, though without providing any mechanistic details (Matsumoto et al., 2023; Noël et al., 2008).

In this study, expressions of AR both at mRNA and protein levels were found to be significantly downregulated in samples from patients, as well as in CC-derived cell lines, like HeLa, SiHa, and CaSki. Exogenous expression of AR followed by ligand (DHT) activation was found to be essential for inhibition of migration and reduction of invasive potential of cervical cancer cells. Further, we showed that AR transcriptionally activates PTEN thereby restoring GSK3β activity, which in turn may facilitates proteasomal degradation of Snail, a transcriptional repressor of the epithelial marker E-cadherin. We also report that exogenous expression and ligand activation of AR make CC cells less motile with the presence of smaller focal adhesions. AR also destabilizes the Actin network via modulating RhoA/ROCK1/LIMK1/CFL1 pathway, uncovering a novel mechanism of AR in cervical cancer. To the best of our knowledge, this is the first report highlighting the plausible mechanisms by which higher abundance and activation of AR could affect cervical cancer progression. Our study leads to avenues for future research in exploring AR supplement followed by DHT or similar synthetic androgen agonist-based activation of AR as potential therapy for cervical cancer.