Molecular Functions of CDK1 in Gastric Tumorigenesis

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ABSTRACT/SUMMARY: Gastric cancer is the third leading cause of cancer-related death worldwide. The 2018 global cancer statistics report indicates an estimated over 1,000,000 new cases and an estimated 783,000 deaths in 2018. Gastric cancers are poorly responsive to therapy and have an unfavorable outcome with an estimated overall 5-year survival rate of approximately 20%. In response to genotoxic stimuli, cancer cells undergo rewiring and reprogramming of transcription and signaling networks to drive adaption and survival properties. This reprogramming leads to the development of acquired adaptive properties that promote survival and expansion of neoplastic cells. Comprehensive analysis approaches have enabled us to identify a biologically relevant novel signaling axis in gastric cancer. We detected aberrant cytosolic overexpression of CDK1 in human and mouse gastric cancers. While CDK1 is a well-established cell cycle regulator, we have discovered previously unreported functions in neoplastic cells in gastric cancer, the focus of this proposal. We found that in response to genotoxic stimuli, such as infection and chemotherapeutics, the surviving pool of neoplastic cells develop an acquired adaptive pro-survival response that includes induction of CDK1 and SOX9 transcription factor. We demonstrate, for the first time, that CDK1 is induced in response to activation of NF-kB transcription activity. At the same time, CDK1 induces SOX9 through epigenetic mechanisms that include activation of DNMT1 and suppression of miR-145. Inhibition of CDK1 by genetic or pharmacologic approaches decreased SOX9 level and activity and induced cancer cell death. Based on novel preliminary results, we hypothesize that activation of CDK1-SOX9 axis promotes cell survival and expansion of neoplastic cells in response to H. pylori infection and chemotherapeutic interventions. We have developed three specific aims that include mechanistic, functional, and translational studies using in vitro models, organoid cultures, mouse models, and de-identified human tissue samples. In aim 1, we plan to investigate the role of H. pylori infection and NF-kB transcription factor in regulating CDK1-SOX9 axis. We will also investigate a novel epigenetic link that includes CDK1 and DNMT1 in regulating SOX9 transcription factor levels and activity. Our second aim will focus on investigating molecular functions and oncogenic transcription network of CDK1-SOX9 axis. The translational significance will be studied in aim 3 by investigating therapeutic potential and clinical significance of CDK1-SOX9 functional axis in gastric cancer. We have assembled a highly collaborative team with experience in advanced molecular technologies, cancer models, and oncology making us in a unique position to perform the proposed studies. Upon completion of this work, we expect to unveil a novel druggable paradigm of cross-talk between CDK1 and SOX9 signaling pathways in gastric tumorigenesis. These molecular interactions not only provide a novel understanding of the biology of gastric cancer but also offer future translational opportunities for the design of new therapeutic interventions for gastric cancer.