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.
Highlights
Cervical cancer is a common female malignancy worldwide, with nearly 600,000 cases and more than 300,000 deaths every year.[1]
In an effort to systemically understand genes related to human papillomavirus (HPV)-negative cervical cancer development (Figure 1A), an analysis of the RNA sequencing (RNA-seq) data identified 1,583 differentially expressed genes between HPV-negative cervical cancer and normal cervical tissues and 3,243 differentially expressed genes between HPV-positive cervical cancer and normal cervical tissues at the cutoff p < 0.01
Some long noncoding RNA (lncRNA) were reported to be downregulated in HPV-negative cervical cancer
Summary
Cervical cancer is a common female malignancy worldwide, with nearly 600,000 cases and more than 300,000 deaths every year.[1]. Some previous studies have revealed the different gene expression patterns of HPV-negative and HPV-positive subtypes of cervical cancers, such as Oct[4], the long noncoding RNA (lncRNA) PVT1, and lncRNA SRA1,9–11 implying that various molecular pathways are involved. These studies did not systematically analyze and verify specific genes related to the development of HPV-negative cervical cancer. We detected the protein expression of these genes by immunohistochemistry (IHC) in HPV-positive cervical cancer tissues compared with HPV-negative cervical cancer tissues and normal control tissues. Identifying novel biomarkers might have the potential to provide novel insights into the specific mechanisms of carcinogenesis in HPV-negative cervical carcinoma
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