Abstract 3868: Six1 overexpression promotes malignant progression in models of cervical and colon cancer

Abstract

Abstract The overexpression of Six1, a member of the Six family of homeodomain transcription factors, has been found in various human cancers, and is associated with increased tumor progression and metastasis. Previous studies in our laboratory discovered that the expression of Six1 mRNA increased during in vitro progression of human papillomavirus type 16 (HPV16) immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. The overexpression of Six1 induced Epithelial-Mesenchymal Transition (EMT) by the activation of p38 MAPK in HKc/DR. Although immortalized and resistant to serum and calcium-induced differentiation, HKc/DR are not tumorigenic. To further explore the role of Six1 in HPV16 immortalized cells we determined whether overexpression of Six1 in HKc/DR resulted in malignant conversion. We found that HKc/DR overexpressing Six1 (DR-Six1), but not HKc/DR controls (DR-Ctrl), formed squamous cell carcinomas in nude mice. Cancer stem cells are proposed to drive tumor initiation and progression; for this reason we analyzed cancer stem cell markers in DR-Ctrl and DR-Six1. We found that DR-Six1 had an increased CD24-/CD44+ population and increased aldehyde dehydrogenase 1 (ALDH1) expression as compared to DR-Ctrl, indicating a cancer stem cell-like phenotype in Six1 overexpressing cells. We then used the human cervical cancer cell line HeLa to further explore the enhanced tumorigenic and malignant properties associated with Six1 overexpression. We determined that overexpressing Six1 in HeLa increased their ability to form spheroids in vitro and increased tumor size in vivo. As an extension of this work, we investigated the role of Six1 on tumorigenesis and metastasis in colon cancer in vivo and in vitro by using the murine colon cancer cell line MC38. We found that Six1 promoted colon cancer tumorigenesis, progression and metastasis, and increased the population of cancer stem cell-like cells. Taken together, our studies demonstrate that Six1 overexpression increases the cancer stem cell-like cell population, and promotes malignant progression in models of cervical and colon cancer. Supported by grant P20MD001770 from the National Institute on Minority Health and Health Disparities. Citation Format: Hanwen Xu, Yu Zhang, Lucia Pirisi, Maria Marjorette Pena, Kim E. Creek. Six1 overexpression promotes malignant progression in models of cervical and colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3868. doi:10.1158/1538-7445.AM2014-3868