HOXD9 Promotes the Growth, Invasion and Metastasis of Gastric Cancer Cells by Transcriptional Activation of RUFY3

Background: The transcription factor HOXD9 is one of the members of the HOX family, which plays an important role in neoplastic processes. However, the role of HOXD9 in the growth and metastasis of gastric cancer (GC) remains to be elucidated.   Methods: In vitro functional role of HOXD9 and RURY3 in GC cells was determined using the TMA-based immunohistochemistry, western blot, EdU incorporation, gelatin zymography, luciferase, chromatin Immunoprecipitation (ChIP) and cell invasion assays. In vivo tumour growth and metastasis were conducted in nude mice.   Findings: HOXD9 is overexpressed in GC cells and tissues. The high expression of HOXD9 was correlated with poor survival in GC patients. Functionally, HOXD9 expression significantly promoted the proliferation, invasion and migration of GC cells. Mechanically, HOXD9 directly associated with the RUFY3 promoter to increase the transcriptional activity of RUFY3. Inhibition of RUFY3 attenuated the proliferation, migration and invasiveness of HOXD9-overexpressing GC cells in vitro and in vivo. Moreover, both HOXD9 and RUFY3 were highly expressed in cancer cells but not in normal gastric tissues, with their expressions being positively correlated. Interpretation: The evidence presented here suggests that the HOXD9-RUFY3 axis promotes the development and progression of human GC. Funding Statement: This study was supported by grants from the National Natural Science Funds of China (Nos.81672875 and 81772964). The funding organization: the Guangzhou Pilot Project of the Clinical and Translational Research Center (early gastrointestinal cancer, No.7415696196402). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: This study was reviewed and approved by the Medical Ethics Committee of Nanfang Hospital (NFEC-2017-062), Southern Medical University, Guangzhou, China. All animal studies were approved by the Institutional Animal Care and Use Committee of Committee of Nanfang Hospital.