Abstract
Discovery of genes and molecular mechanism involved in cervical cancer development would promote the prevention and treatment. By comparing gene expression profiles of cervical carcinoma in situ (CCIS) and adjacent normal tissues, we identified a potential cancer-promoting gene, IMPA2. This study aimed to elucidate the role of IMPA2 and underlying molecular mechanisms in cervical cancer progression. To do this expression of IMPA2 was compared between human cervical cancer and corresponding adjacent normal cervical tissues firstly. CCK-8 assay, clone formation assay, wound healing assay, transwell assay, and tumor formation in nude mice were performed to demonstrate the effect of IMPA2 in cervical cancer proliferation and metastasis. Further proteomic profiling and western blotting explored the molecular pathway involved in the IMPA2-regulating process. The results showed that IMPA2 gene expression was upregulated in cervical cancer. Consistently, silencing of IMPA2 suppressed tumor formation in BALB/c nude mice. Short hairpin RNA (shRNA)-mediated IMPA2 silencing significantly inhibited proliferation and colony-forming abilities of cervical cancer cells, while IMPA2 overexpression had little impact. Also, IMPA2 silencing suppressed cellular migration, but overexpression promoted migration. Proteomics analysis revealed the involvement of mitogen-activated protein kinase (MAPK) pathway in tumor-promoting action of IMPA2. Significantly, the inhibition of IMPA2 activated ERK phosphorylation, and its inhibitory effects can be restored by using selective ERK inhibitor, FR180204. In conclusion, IMPA2 acts as an oncogene in the proliferation and migration of cervical cancer. IMPA2 downregulated ERK phosphorylation to promote cervical cancer. These findings identify a new mechanism underlying cervical cancer and suggest a regulating effect of IMPA2 in MAPK signaling pathway.
Highlights
Cervical cancer is the fourth leading cause of cancerassociated death regarding gynecological malignancies worldwide[1], even though prevention and treatment have rapidly developed recently[2,3]
inositol monophosphatase 2 (IMPA2) is overexpressed in cervical cancer Comparing the gene expression profiles of carcinoma in situ (CCIS) and adjacent normal cervical samples resulted in 1555 differentially regulated genes at P < 0.05
Expression of IMPA2 was compared among cervical cancer cell lines and normal cervical epithelial cell line to prove the overexpression (Fig. 1e, f)
Summary
Cervical cancer is the fourth leading cause of cancerassociated death regarding gynecological malignancies worldwide[1], even though prevention and treatment have rapidly developed recently[2,3]. The most significant cause of cervical cancer is persistent infection of human papillomavirus (HPV). RNA sequencing provides an efficient and comprehensive method to identify the key genes and molecular pathways involved in cervical cancer pathogenesis[7,8]. By comparing gene expression profiles of CCIS and adjacent normal tissues, it is possible to look for the most direct evidence of tumorigenesis and help early diagnosis. We sought potential oncogenes of cervical cancer, by comparing mRNA expression profiles of tissue samples of CCIS with adjacent normal cervical tissue. IMPA2 gene was discovered to be significantly upregulated in CCIS tissues.
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