Int J Biol Sci 2021; 17(2):514-526. doi:10.7150/ijbs.54074 This issue
1. Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
2. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
3. Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
4. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
5. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin Medical University, Harbin, China
#These authors contributed to the work equally and should be regarded as co-first authors
Proliferation is one of the significant hallmarks of gallbladder cancer, which is a relatively rare but fatal malignance. Aim of this study was to examine the biological impact and molecular mechanism of the candidate hub-gene on the proliferation and tumorigenesis of gallbladder cancer. We analyzed the differentially expressed genes and the correlation between these genes with MKI67, and showed that KIF11 is one of the major upregulated regulators of proliferation in gallbladder cancer (GBC). The Gene Ontology, Gene Sets Enrichment Analysis and KEGG Pathway analysis indicated that KIF11 may promote GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. Gain-of-function and loss-of-function assay demonstrated that KIF11 regulated GBC cell cycle and cancer cell proliferation in vitro. GBC cells exhibited G2M phase cell cycle arrest, cell proliferation and clone formation ability reduction after treatment with Monastrol, a specific inhibitor of KIF11. Xenograft model showed that KIF11 promotes GBC growth in vivo. Rescue experiments showed that KIF11-induced GBC cell proliferation dependented on ERBB2/PI3K/AKT pathway. Moreover, we found that H3K27ac signals are enriched among the promoter region of KIF11 in the UCSC Genome Browser Database. Differentially expressed analysis showed that EP300, a major histone acetyltransferase modifying H3K27ac signal, is highly expressed in gallbladder cancer and correlation analysis illustrated that EP300 is positively related with KIF11 in almost all the cancer types. We further found that KIF11 was significantly downregulated in a dose-dependent and time-dependent manner after histone acetylation inhibitor treatment. The present results highlight that high KIF11 expression promotes GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. The findings may help deepen our understanding of mechanism underlying GBC cancer development and development of novel diagnostic and therapeutic target.