Discovery of key genes as novel biomarkers specifically associated with HPV-negative cervical cancer

Yi Liu; Yichi Xu; Wenxiao Jiang; Huihui Ji; Zhi-Wei Wang; Xueqiong Zhu

doi:10.1016/j.omtm.2021.03.026

Discovery of key genes as novel biomarkers specifically associated with HPV-negative cervical cancer

Mol Ther Methods Clin Dev. 2021 Apr 6:21:492-506. doi: 10.1016/j.omtm.2021.03.026. eCollection 2021 Jun 11.

Authors

Yi Liu^{1

2}, Yichi Xu¹, Wenxiao Jiang¹, Huihui Ji¹, Zhi-Wei Wang¹, Xueqiong Zhu¹

Affiliations

¹ Center of Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
² Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Abstract

Cervical cancer is a common female malignancy that is mainly caused by human papillomavirus (HPV) infection. However, the incidence of HPV-negative cervical cancer has shown an increasing trend in recent years. Because the mechanism of HPV-negative cervical cancer development is unclear, this study aims to find the pattern of differential gene expression in HPV-negative cervical cancer and verify the underlying potential mechanism. Differentially expressed genes were compared among HPV-positive cervical cancer, HPV-negative cervical cancer, and normal cervical tissues retrieved from TCGA. Subsequently, dysregulated differentially expressed genes specifically existed in HPV-negative cervical cancer tissues and HPV-negative cell lines were validated by qRT-PCR, western blotting, and immunohistochemical staining. We found seventeen highly expressed genes that were particularly associated with HPV-negative cervical cancer from analysis of TCGA database. Among the 17 novel genes, 7 genes (preferentially expressed antigen in melanoma [PRAME], HMGA2, ETS variant 4 [ETV4], MEX3A, TM7SF2, SLC19A1, and tweety-homologs 3 [TTYH3]) displayed significantly elevated expression in HPV-negative cervical cancer cells and HPV-negative cervical cancer tissues. Additionally, higher expression of MEX3A and TTYH3 was associated with a shorter overall survival of patients with HPV-negative cervical cancer. Our study implies that these seven genes are more likely to provide novel insights into the occurrence and progression of HPV-negative cervical cancer.

Keywords: ETV4; HMGA2; HPV-negative cervical cancer; HPV-positive cervical cancer; MEX3A; PRAME; TTYH3; prognosis; therapy.