Abstract
Metabolic reprogramming is one of the emerging hallmarks of cancer cells. Various factors, such as signaling proteins (S), miRNA, and transcription factors (TFs), may play important roles in altering the metabolic status in cancer cells by interacting with metabolic enzymes either directly or via protein-protein interactions (PPIs). Therefore, it is important to understand the coordination among these cellular pathways, which may provide better insight into the molecular mechanism behind metabolic adaptations in cancer cells. In this study, we have designed a cervical cancer-specific supra-interaction network where signaling pathway proteins, TFs, and microRNAs (miRs) are connected to metabolic enzymes via PPIs to investigate novel molecular targets and connections/links/paths regulating the metabolic enzymes. Using publicly available omics data and PPIs, we have developed a Hidden Markov Model (HMM)-based mathematical model yielding 94, 236, and 27 probable links/paths connecting signaling pathway proteins, TFs, and miRNAs to metabolic enzymes, respectively, out of which 83 paths connect to six common metabolic enzymes (RRM2, NDUFA11, ENO2, EZH2, AKR1C2, and TYMS). Signaling proteins (e.g., PPARD, BAD, GNB5, CHECK1, PAK2, PLK1, BRCA1, MAML3, and SPP1), TFs (e.g., KAT2B, ING1, MED1, ZEB1, AR, NCOA2, EGR1, TWIST1, E2F1, ID4, RBL1, ESR1, and HSF2), and miR (e.g., mir-147a, mir-593-5p, mir-138-5p, mir-16-5p, and mir-15b-5p) were found to regulate two key metabolic enzymes, EZH2 and AKR1C2, with altered metabolites (L-lysine and tetrahydrodeoxycorticosterone, THDOC) status in cervical cancer. We believe, the biology-based approach of our system will pave the way for future studies, which could be aimed toward identifying novel signaling, transcriptional, and post-transcriptional regulators of metabolic alterations in cervical cancer.
Highlights
Cervical cancer is the fourth most frequently occurring cancer and the fourth leading cause of death in women worldwide with an estimate of 5,70,000 cases and 3,11,000 deaths in 2018
Microtubule cytoskeleton organization involved in mitosis (p = 2.13E−14) and peptide cross-linking (p = 8.81E−11) were highly enriched biological processes, for upregulated gene-encoded proteins and downregulated gene-encoded proteins, respectively (Supplementary Figure 1)
Understanding the molecular mechanisms for cancer progression and subsequent development of potential therapeutics to inhibit this complex disease are difficult from the independent knowledge of ongoing signaling, gene regulatory, and metabolic alterations
Summary
Cervical cancer is the fourth most frequently occurring cancer and the fourth leading cause of death in women worldwide with an estimate of 5,70,000 cases and 3,11,000 deaths in 2018. Squamous cell carcinoma (SCC) and adenocarcinomas are the two main types of cervical cancer. 90% of patients with cervical cancer belong to SCC [3]. The persistent infection with human papillomavirus (HPV), a high-risk type of HPV (mainly HPV16 and HPV18 type), is considered the primary cause of cervical cancer [4,5,6]. HPV16 and HPV18 types are responsible for almost 70% of cases of cervical cancer globally [7]. While infection by highrisk HPV is necessary for developing cervical cancer, it alone may not be sufficient. Various studies suggest that the pathogenesis of cervical cancer depends on various other factors acting in concert with disease-associated HPV types [8,9,10]. It is important to understand the molecular mechanism behind the development of cervical cancer
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