Weighted Gene Co-expression Network Analysis Unveiled Key Genes Related to Progression and Prognosis of Cervical Cancer

Document Type : Research Article


Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran


Cervical cancer is one of the most common malignancies and one of the main death causes among females all over the world. The discovery of tumor-related genes is crucial for understanding tumor biology and developing preventative and therapeutic strategies. However, genes included in the tumorigenesis of cervical cancer cells are still unclear. Due to its high prevalence and mortality, understating its pathogenesis and biomarker detection is necessary. The purpose of this study was to recognize potential biomarkers related to cervical cancer and analyze their prognostic significance. The present research used the level 3 mRNA expression data and clinical data of cervical cancer from The Cancer Genome Atlas database to identify differentially expressed genes followed by gene ontology. Weighted co-expression Network Analysis was used to construct scale-free gene co-expression networks. In the co-expression network, the hub module and hub genes were identified. The significant modules associated with T, N, M, and FIGO staging in the network were subsequently screened. Next, overlapping genes between significant gene modules and DEGs were screened. CALML5, TERT, PNPLA3, CHRDL1, C7, LEFTY2, and PCP4 were identified as hub genes. Survival analysis was performed to identify the association between these genes and survival using the GEPIA database. Survival analysis showed that PCP4 was slightly less expressed in patients with primary solid tumors than normal, and related to poor prognosis in cervical cancer. These results show that these hub genes, especially PCP4, may be a potential diagnostic biomarker for cervical cancer and provide a new perspective on the pathogenesis of cervical cancer.


Main Subjects

Alowayed N, Salker MS, Zeng N, Singh Y, Lang F. 2016. LEFTY2 controls migration of human endometrial cancer cells via focal adhesion kinase activity (FAK) and miRNA-200a. Cell Physiol Biochem 39(3): 815-826.
Barroso S, Rieubland C, JoséÁlvarez A, López‐Trascasa M, Bart PA, Núñez‐Roldán A, …, Sánchez B. 2006. Molecular defects of the C7 gene in two patients with complement C7 deficiency. Immunology 118(2): 257-260.
BasuRay S, Wang Y, Smagris E, Cohen JC, Hobbs HH. 2019. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci 116(19): 9521-9526.
Boeker M, França F, Bronsert P, Schulz S. 2016. TNM-O: ontology support for staging of malignant tumours. J Biomed Semant 7: 1-11.
Chang PA, Sun YJ, Huang FF, Qin WZ, Chen YY, Zeng X, …, Wu YJ. 2013. Identification of human patatin-like phospholipase domain-containing protein 1 and a mutant in human cervical cancer HeLa cells. Mol Biol Rep 40: 5597-5605.
Chen L, Lu D, Sun K, Xu Y, Hu P, Li X, …, Xu F. 2019. Identification of biomarkers associated with diagnosis and prognosis of colorectal cancer patients based on integrated bioinformatics analysis. Gene 692: 119-125.
Chen X, Huang L, Yang Y, Chen S, Sun J, Ma C, …, Yang J. 2020. ASPM promotes glioblastoma growth by regulating G1 restriction point progression and Wnt-β-catenin signaling. Aging (Albany NY) 12(1): 224-241.
Debald M, Schildberg FA, Linke A, Walgenbach K, Kuhn W, Hartmann G, …, Walgenbach-Bruenagel G. 2013. Specific expression of k63-linked ubiquitination of calmodulin-like protein 5 in breast cancer of premenopausal patients. J Cancer Res Clin Oncol 139: 2125-2132.
Denny L. 2015. Control of cancer of the cervix in low-and middle-income countries. Ann Surg Oncol 22: 728-733.
Di Y, Chen D, Yu W, Yan L. 2019. Bladder cancer stage-associated hub genes revealed by WGCNA co-expression network analysis. Hereditas 156(1): 1-11.
Dickinson A, Saraswat M, Syrjänen S, Tohmola T, Silén R, Randén-Brady R, …, Mattila P. 2020. Comparing serum protein levels can aid in differentiating HPV-negative and-positive oropharyngeal squamous cell carcinoma patients. PLoS One 15(6): e0233974.
Edgar R, Barrett T. 2006. NCBI GEO standards and services for microarray data. Nat Biotechnol 24(12): 1471-1472.
Hamada T, Souda M, Yoshimura T, Sasaguri S, Hatanaka K, Tasaki T, …, Tsutsui M. 2014. Anti-apoptotic effects of PCP4/PEP19 in human breast cancer cell lines: a novel oncotarget. Oncotarget 5(15): 6076-6086
Ibeanu OA. 2011. Molecular pathogenesis of cervical cancer. Cancer Biol Ther 11(3): 295-306.
Kitazawa S, Takaoka Y, Ueda Y, Kitazawa R. 2021. Identification of calmodulin‐like protein 5 as tumor‐suppressor gene silenced during early stage of carcinogenesis in squamous cell carcinoma of uterine cervix. Int J Cancer 149(6): 1358-1368.
Kumar L, Harish P, Malik PS, Khurana S. 2018. Chemotherapy and targeted therapy in the management of cervical cancer. Curr Probl Cancer 42(2): 120-128.
Langfelder P, Horvath S. (2008). WGCNA: an R package for weighted correlation network analysis. BMC Bioinform 9(1): 1-13.
Lu X, Song X, Hao X, Liu X, Zhang X, Yuan N, …, Zhang Z. 2021. MiR-186-3p attenuates tumorigenesis of cervical cancer by targeting IGF1. World J Surg Oncol 19(1): 1-10.
Mamoor S. 2021. Differential expression of CHRDL1 in cancer of the vulva. doi:10.31219/osf.io/6mnkr
Orlov YL, Baranova AV. 2020. Bioinformatics of genome regulation and systems biology. Front Genet 11:625. doi.org/10.3389/fgene.2020.00625
Pestana A, Vinagre J, Sobrinho-Simões M, Soares P. 2017. TERT biology and function in cancer: beyond immortalisation. J Mol Endocrinol 58(2): 129-146.
Petry KU. 2014. HPV and cervical cancer. Scand. J Clin Lab 74(244): 59-62.
Sharma S, Deep A, Sharma AK. 2020. Current treatment for cervical cancer: an update. Anti-Cancer Agents Med Chem. 20(15): 1768-1779.
Sookoian S, Pirola CJ. 2014. PNPLA3, the history of an orphan gene of the potato tuber protein family that found an organ: the liver. Hepatol 59(6): 2068-2071.
Tamura G. 2006. Alterations of tumor suppressor and tumor-related genes in the development and progression of gastric cancer. World J Gastroenterol 12(2): 192.
Tomczak K, Czerwińska P, Wiznerowicz M. 2015. Review The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol 2015(1): 68-77.
Vu M, Yu J, Awolude OA, Chuang L. 2018. Cervical cancer worldwide. Curr Probl Cancer 42(5): 457-465.
Wang F, Nazarali AJ, Ji S. 2016. Circular RNAs as potential biomarkers for cancer diagnosis and therapy. Am J Cancer Res 6(6): 1167-1176.
Wang Jy, Chen Lj. 2019. The role of miRNAs in the invasion and metastasis of cervical cancer. Biosci Rep 39(3). doi: 10.1042/BSR20181377
Webb TR, Matarin M, Gardner JC, Kelberman D, Hassan H, Ang W, …, Hardcastle AJ. 2012. X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development. Am J Hum Genet 90(2): 247-259.
Wright JD, Chen L, Tergas AI, Burke WM, Hou JY, Neugut AI, …, Hershman DL. 2015. Population-level trends in relative survival for cervical cancer. Am J Obstet Gynecol 213(5): 670. e1-670. e7.
Yin X, Wang P, Yang T, Li G, Teng X, Huang W, …, Yu H. 2021. Identification of key modules and genes associated with breast cancer prognosis using WGCNA and ceRNA network analysis. Aging (Albany NY) 13(2): 2519.
Ying L, Zhang F, Pan X, Chen K, Zhang N, Jin J, …, Jin H. 2016. Complement component 7 (C7), a potential tumor suppressor, is correlated with tumor progression and prognosis. Oncotarget 7(52): 86536-86546.
Yoshimura T, Hamada T, Hijioka H, Souda M, Hatanaka K, Yoshioka T, …, Tanimoto A. 2016. PCP4/PEP19 promotes migration, invasion and adhesion in human breast cancer MCF-7 and T47D cells. Oncotarget 7(31): 49065-49074.
Zhai X, Xue Q, Liu Q, Guo Y, Chen Z. 2017. Colon cancer recurrence‑associated genes revealed by WGCNA co‑expression network analysis. Mol Med Rep 16(5): 6499-6505.
Zou H, Chen H, Liu S, Gan X. 2021. Identification of a novel circ-0018289/miR-183-5p/TMED5 regulatory network in cervical cancer development. World J Surg Oncol 19(1): 1-13.