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

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.

Human papillomavirus independent status on pathologic response and outcomes in locally advanced cervical cancer managed with chemoradiotherapy followed by surgery

“…Interest in HPV independent cervical cancer has increased in recent years 5–10. Data published on head and neck cancer, as well as improvements in histological diagnosis using molecular characterization, have contributed to this interest 30–34. Controversy concerning HPV independent cervical cancer exists relating to the heterogeneity of stage and histotypes throughout these studies, as well as differences in therapeutic approaches, poor quality of tissue samples, and differences among HPV detection methods 35…”

A Novel Identified Long Intergenic Noncoding RNA, LINC01574, Contributes to Breast Cancer Deterioration via the Regulation of miR-6745/TTYH3 Axis

“…For example, in cholangiocarcinoma, high expression of TTYH3 accelerated ETM transformation and promoted malignant behavior of cholangiocarcinoma cells [37]. In ovarian cancer, cervical cancer, and colorectal cancer, elevated expression of TTYH3 also predicted poor prognosis [38][39][40]. Interestingly, we found that overexpression of TTYH3 also evidently facilitated the malignant phenotype of BC, manifested by enhanced proliferative and metastatic abilities.…”

Targeted RNA next generation sequencing analysis of cervical smears can predict the presence of hrHPV-induced cervical lesions

“…Also, the cancer genome atlas (TCGA) includes several HPV-negative cervix carcinomas [ 15 ]. Studies have shown that gene expression profiles of these cancers are distinct from those of HPV-positive cervical cancers, providing evidence that HPV-negative cervical cancers comprise a separate entity [ 43 ]. These cancers will be missed in screening programs that use HPV screening as a primary test.…”