Abstract
Even though infection with human papillomaviruses (HPV) is very important, it is not the sole cause of cervical cancer. Because it is known that genetic variations that result from HPV infection are probably the most important causes of cervical cancer, we used human whole genome array comparative genomic hybridization to detect the copy number variations of genes in cervical squamous cell carcinoma. The results of the array were validated by PCR, FISH and immunohistochemistry. We find that the copy number and protein expression of claudin-1 (CLDN1) increase with the progression of cervical cancer. The strong positive staining of CLDN1 in the cervical lymph node metastasis group received a significantly higher score than the staining in the group with no lymph node metastasis of cervical cancer tissues. The overexpression of CLDN1 in SiHa cells can increase anti-apoptosis ability and promote invasive ability of these cells accompanied by a decrease in expression of the epithelial marker E-cadherin as well as an increase in the expression of the mesenchymal marker vimentin. CLDN1 induces the epithelial-mesenchymal transition (EMT) through its interaction with SNAI1. Furthermore, we demonstrate that CLDN1 overexpression has significant effects on the growth and metastasis of xenografted tumors in athymic mice. These data suggest that CLDN1 promotes invasion and metastasis in cervical cancer cells via the expression of EMT/invasion-related genes. Therefore, CLDN1 could be a potential therapeutic target for the treatment of cervical cancer.
Highlights
With the introduction of population-wide screening programs, the worldwide incidence and mortality rate of cervical cancer have continued to decline
Because it is known that genetic variations that result from human papillomaviruses (HPV) infection are probably the most important causes of cervical cancer, we used human whole genome array comparative genomic hybridization to detect the copy number variations of genes in cervical squamous cell carcinoma
The results showed that copy number gains were most frequently observed by array comparative genomic hybridization (CGH) at 3q27.3-3q29 (60%), 11q12.311q13.1 (50%), 3q23 (40%), xq28 (40%), 3q24-3q26.32 (30%), 5p15.1-5p15.3 (30%), 9q32-9q33.2 (30%), and 8q24.21 (20%) (Table 1)
Summary
With the introduction of population-wide screening programs, the worldwide incidence and mortality rate of cervical cancer have continued to decline. Persistent infection with high-risk human papillomavirus (HPV) is recognized as a necessary initiating event but not a sufficient event in cervical carcinogenesis [2]. The integration of HPV into the human genome is recognized as an important basis for cervical carcinogenesis [3]. The high-risk forms of HPV can induce genomic instability, such as chromosome segregation, aneuploidy, and structural chromosome aberrations, in normal human cells, which is one of the hallmarks of a cancer cell. This activity is likely to be functionally correlated to the contribution of high-risk HPV to malignant progression [4]
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