title: USP7 promotes cell proliferation through the stabilization of Ki-67 protein in non-small cell lung cancer cells.
abstract: The Ki-67 antigen (Ki-67) is the most reliable immunohistochemical marker for evaluation of cell proliferation in non-small cell lung cancer. However, the mechanisms underlying the regulation of protein levels of Ki-67 in non-small cell lung cancer have remained elusive. In this study, we found that Ki-67 and ubiquitin-specific processing protease 7 (USP7) protein were highly expressed in the nucleus of non-small cell lung cancer cells. Furthermore, statistical analysis uncovered the existence of a strong correlation between Ki-67 and USP7 levels. We could also show that the protein levels of Ki-67 in non-small cell lung cancer cells significantly decreased after treatment with P22077, a selective chemical inhibitor of USP7, while the Ki-67 mRNA levels were unperturbed. Similar results were obtained by knocking down USP7 using short hairpin RNA (shRNA) in lung cancer cells. Interestingly, we noticed that ubiquitination levels of Ki-67 increased dramatically in USP7-silenced cells. The tests in vitro and vivo showed a significant delay in tumor cell growth upon knockdown of USP7. Additionally, drug sensitivity tests indicated that USP7-silenced A549 cells had enhanced sensitivity to paclitaxel and docetaxel, while there was no significant change in sensitivity toward carboplatin and cisplatin. Taken together, these data strongly suggest that the overexpression of USP7 might promote cell proliferation by deubiquitinating Ki-67 protein, thereby maintaining its high levels in the non-small cell lung cancer. Our study also hints potential for the development of deubiquitinase-based therapies, especially those targeting USP7 to improve the condition of patients diagnosed with non-small cell lung cancer.
authors: Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Rd, Shanghai 200011, China.
authors: Chao
authors: C
authors: Zhang
authors: Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Rd, Shanghai 200011, China.
authors: Jing
authors: J
authors: Lu
authors: Department of Pathology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China.
authors: Quan-Wu
authors: QW
authors: Zhang
authors: Department of Pathology, The First People's Hospital of Changzhou (The Third Affiliated Hospital of Soochow University), Changzhou 213003, China.
authors: Wei
authors: W
authors: Zhao
authors: Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Rd, Shanghai 200011, China.
authors: Jia-Hui
authors: JH
authors: Guo
authors: Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Rd, Shanghai 200011, China.
authors: Shan-Ling
authors: SL
authors: Liu
authors: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Ying-Li
authors: YL
authors: Wu
authors: Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Rd, Shanghai 200011, China. Electronic address: dr_jiang@yeah.net.
authors: Bin
authors: B
authors: Jiang
authors: Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Rd, Shanghai 200011, China. Electronic address: fenghougao@163.com.
authors: Feng-Hou
authors: FH
authors: Gao
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019610:Cytoprotection; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D055550:Protein Stability; D000076084:Ubiquitin-Specific Peptidase 7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019394:Ki-67 Antigen; C464569:USP7 protein, human; D000076084:Ubiquitin-Specific Peptidase 7
keywords: Cell proliferation; Ki-67; Non-small cell lung cancer; USP7; Ubiquitination