Functional Investigation of Heat Shock Protein in Esophageal Squamous Cell Cancer with Implications in Prognostic Prediction and Therapeutic Targeting

Esophageal cancer is a common cancer worldwide and it is associated with poor prognosis. The development of cancer in humans is an intricate multistep process that involves progressive accumulation of abnormalities in expression of multiple genes, including activation of oncogenes. Recent studies have shown that heat shock proteins (HSPs), induced under stress conditions, may play an important role in cancer development and tumor progression and may serve as a target for cancer therapy. Overexpression of HSP expression in cancer cells plays a pivotal role in preventing spontaneous apoptosis and apoptosis induced by therapy. Little is known on how HSP dysregulation affects the molecular events involved with tumor growth, invasiveness, and metastasis. The link between HSPs and cancer is increasingly heighted in recent years and related studies have led to development of novel therapeutic agents. Among all HSP family proteins, HSP70 and HSP90 are the most studied ones and their expression serve as predictor for poor prognosis in a wide range of cancers. Notably, HSP90 plays a particularly versatile role in regulation of cellular function involving in the formation of with a large number of kinases, transcription factors, and other molecules. .Hypoxia is known as a hallmark of solid tumors and the extent of tumor hypoxia is associated with resistance to treatment and poor prognosis. Cells respond to this stress by expressing a group of proteins known as hypoxia inducible factors (HIFs). There were only limited studies showing that HSP90 interacts with HIF-1α. To date, there has been lack of studies on the role of HSP in esophageal squamous cell carcinoma (ESCC) in terms of its prognostic significance, its role in tumor progression, invasion, metastasis and angiogenesis with investigations to its cross talk with other signaling pathway. Further, we aim to test if HSP, focusing on HSP90, may serve as a therapeutic target using in vitro and in vivo animal models. We design this 3-year project to address our study interests as highlighted above. In year 1, we first study correlation between expression of HSP in resected ESCC with clinicopathologic parameters to determine it prognostic significance. To support observations from clinicopathologic correlative studies, a culture system using 2 selected ESCC cell lines to test if the role of HSP in ESCC cell lines in vitro by a pharmacologic approach using 17-DMAG, a potent HSP90 inhibitor under clinical trials, to test its effects on cell survival, migration, and invasion along with potential regulation of angiogenic factors in selected esophageal cancer cell lines. In year 2, extending results from the 1st year project, we aim to investigate potential cross-talks between HSP and HIF in tumor hypoxia in vitro by employing a pharmacologic approach using HSP90 inhibitor (i.e.17-DMAG) and a novel HIF-1 inhibitor, FM19G11. In addition, pathways that might link with HSP will also be examined in this year project. In year 3, Representative ESCC cell lines with highly expressed HSP90 will be will be used for in vivo tumor xenograft studies to validate our in vitro results from projects of Year 1 and Year 2. Hopefully, this study will allow us to understand better the functional role of HSP and its link to signaling pathway related to oncogenesis and tumor progression with implication of its potential as a target therapy in ESCC.