The biological function and clinical significance of STAT1 in esophageal squamous cell carcinoma

• Author / Creator

  Zhang, Ying

• Although esophageal cancer makes up only 1% of all the cancers in western countries, it is a common death cancer in other areas, especially China. Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer in Chaoshan, an area with high incidence rate of this disease in China. However, the pathogenesis of ESCC is incompletely understood until now. Signal transducer and activator of transcription 1 (STAT1) is considered as a tumor suppressor in many types of cancer, such as breast cancer and melanoma. However, the biological and clinical significance of STAT1 in ESCC has never been clearly demonstrated. In this thesis, I hypothesized that STAT1 plays a tumor suppressor role in ESCC via distinct mechanisms, including activavtion of downstream genes and interaction with some other factors. I found that constitutive activated STAT1 induced cell apoptosis, cell growth inhibition and cell cycle arrest in ESCC cell lines, whereas, knockdown of STAT1 led to the opposite results. The in-vivo study revealed that STAT1 is downregulated in ESCC compared to case-matched normal esophageal epithelial tissues. Importantly, the loss of STAT1 correlated with a worse clinical outcome in a large cohort of ESCC patients. In addition, STAT1 can regulate several apoptosis and cell cycle target genes, such as BCL-xL, p21, cyclin D1, which was also confirmed by using immunohistochemistry in ESCC patient samples. Then we found that ERK was an effective negative regulator of STAT1 signaling in ESCC, by promoting its proteasomal degradation and decreasing IFN-γ production. The correlation and clinical significance of STAT1 and ERK were confirmed by using immunohistochemistry in a large cohort of ESCC patients. Finally, we examined the cross-regulation of STAT1α and STAT1β, two isoforms of STAT1 in ESCC. STAT1β was found to enhance the tumor suppressor function of STAT1 by interacting with STAT1α to protect it from protein degradation. The clinical significance of STAT1β was also explored in a large cohort of ESCC patient samples, which confirmed the hypothesis that STAT1β plays a tumor suppressor role in ESCC. All together, this study provides novel insights into the biological function and clinical significance of STAT1 in ESCC, which favors to understand the importance of STAT1 signaling in cancer. These findings have provided new therapeutic strategies for ESCC by targeting STAT1. We may predict the survival of ESCC patients based on the STAT1 expression. In addition, the anti-tumor drugs, aiming at activating STAT1, could be designed to treat the ESCC patients.

• Subjects / Keywords

  • Esophageal squamous cell carcinoma
  • STAT1

• Graduation date

  Fall 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3RV0D80V

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.