Abstract
If left untreated, a subset of high-grade squamous intraepithelial lesions (HSIL) of the cervix will progress to invasive squamous cell carcinomas (SCC). To identify genes whose differential expression is linked to cervical cancer progression, we compared gene expression in microdissected squamous epithelial samples from 10 normal cervices, 7 HSILs, and 21 SCCs using high-density oligonucleotide microarrays. We identified 171 distinct genes at least 1.5-fold up-regulated (and P < 0.001) in the SCCs relative to HSILs and normal cervix samples. Differential expression of a subset of these genes was confirmed by quantitative reverse transcription-PCR and immunohistochemical staining of cervical tissue samples. One of the genes up-regulated during progression, HOXC10, was selected for functional studies aimed at assessing its role in mediating invasive behavior of neoplastic squamous epithelial cells. Elevated HOXC10 expression was associated with increased invasiveness of human papillomavirus-immortalized keratinocytes and cervical cancer-derived cell lines in both in vitro and in vivo assays. Cervical cancer cells with high endogenous levels of HOXC10 were less invasive after short hairpin RNA-mediated knockdown of HOXC10 expression. Our findings support a key role for the HOXC10 homeobox protein in cervical cancer progression. Other genes with differential expression in invasive SCC versus HSIL may contribute to tumor progression or may be useful as markers for cancer diagnosis or progression risk.
Highlights
Cervical cancer is the third leading cause of cancer deaths in women worldwide, with increased mortality in less developed regions compared with the industrialized world
To determine whether the amplified cRNA from the samples accurately represent the relative abundance of mRNAs in the starting material, we compared the gene expression profile from 5 Ag of RNA sample extracted from a primary cervical carcinoma (C-2T) undergoing a single round of in vitro transcription (IVT), to a 100 ng sample of RNA from the same specimen amplified with two rounds of IVT
To assess effects of laser capture microdissection (LCM) on gene expression profiling, we compared gene expression from the 100 ng C-2T sample above, isolated from a tumor cell-rich region without LCM, and 30 ng of total RNA were isolated from C-2T by LCM, both using two rounds of IVT
Summary
Cervical cancer is the third leading cause of cancer deaths in women worldwide, with increased mortality in less developed regions compared with the industrialized world. Identification of molecular markers defining the subset of HSILs at high risk for progression could clearly affect management of preinvasive cervical lesions. To identify genes associated with the invasive properties of cervical carcinoma cells, we used high-density (Affymetrix U133A) oligonucleotide microarrays to generate comprehensive gene expression profiles of microdissected epithelial samples from normal cervices, HSILs, and invasive squamous cell carcinomas (SCC) of the cervix. Comparison of gene expression in the preinvasive and invasive epithelial neoplasms identified a rather modest number of genes differentially up-regulated or downregulated in SCCs relative to HSILs and normal cervical squamous epithelia. Our differential expression screen identified several genes that may prove useful as diagnostic or progression markers for cervical cancer; a subset of these genes encodes proteins that confer invasive properties to neoplastic cervical epithelial cells. I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-2056
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