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KRASG12C mutation-induced TOPK overexpression contributes to tumour progression in non-small cell lung cancer |
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| Authors: | Chang Cai Shuo Yao Yanmei Zou Hui Lu Xiuqiong Chen Yali Wang Kun Zheng Feng Zhu Yihua Wang Hua Xiong Junfei Zhu |
| Affiliation: | 1. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China Contribution: Methodology (lead), Data curation (lead), Formal analysis (lead), Writing - original draft (lead), Project administration (lead);2. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Methodology (lead), Writing - original draft (lead), Writing - review & editing (lead);3. Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Data curation (equal), Formal analysis (equal), Supervision (equal);4. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Data curation (equal), Formal analysis (equal), Investigation (equal);5. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Formal analysis (equal), Validation (equal);6. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Contribution: Formal analysis (equal), Visualization (equal);7. Cancer Research Institute, The Affiliated Hospital of Guilin Medical University, Guilin, China Contribution: Investigation (equal), Resources (equal);8. Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK Institute for Life Sciences, University of Southampton, Southampton, UK NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK Contribution: Conceptualization (lead), Data curation (lead), Project administration (equal), Writing - review & editing (equal);9. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;10. Department of Respiratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China |
| Abstract: | KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRASG12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRASG12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRASG12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRASG12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics. |
| Keywords: | KRASG12C NSCLC proliferation TOPK |