OncoTargets and Therapy (Nov 2019)
Aberrantly High Expression Of NOK/STYK1 Is Tightly Associated With The Activation Of The AKT/GSK3β/N-Cadherin Pathway In Non-Small Cell Lung Cancer
Abstract
Zhao Huang,1,* Nan Ma,2,* Yan-Lu Xiong,1,* Lei Wang,1 Wei-Miao Li,1 Yuan-Yang Lai,1 Chen-Xi Zhang,1 Zhi-Pei Zhang,1 Xiao-Fei Li,1 Jin-Bo Zhao1 1Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038, People’s Republic of China; 2Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jin-Bo Zhao; Xiao-Fei LiDepartment of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Baqiao, Xi’an, Shaanxi 710038, People’s Republic of ChinaTel +86 29 8471 7367Fax +86 29 8471 7367Email [email protected]; [email protected]: High metastasis is a leading risk factor for the survival of non-small cell lung cancer (NSCLC) and epithelial-mesenchymal transition (EMT) is a vital step of metastasis. The expression of novel oncogene with kinase domain (NOK) has been observed in some human malignancies, including non-small cell lung cancer (NSCLC); however, the biological function of NOK in NSCLC remains unclear. In the study, we explored the function of NOK in NSCLC, with an aim to elucidate the relevant underlying mechanisms.Patients and methods: We investigate the expression of NOK, p-Akt, p-GSK-3β, E-cadherin and N-cadherin expression by immunohistochemical analysis using tissue microarrays of 72 paired NSCLC samples of cancerous and adjacent normal tissues. The associations between NOK expression and clinicopathological factors, overall survival, other proteins were assessed. Immunofluorescence analysis of NSCLC tissues was performed to study the location of NOK, Akt and GSK-3β. Up or down-regulated of NOK were conducted in two NSCLC cell lines to analyze its impact on AKT/GSK3β pathway.Results: Statistical analysis revealed NOK expression increased in NSCLC tissues compared with normal tissues (P<0.05). It also showed that low NOK expression were associated with a higher possibility of non-lymphatic metastasis, an early pN stage and clinical stage (P<0.05). Moreover, NOK expression was positively correlated with the expression of oncogene p-Akt (Thr308), p-GSK-3β (Ser9) and N-cadherin (P<0.05). Immunofluorescence analysis of NSCLC tissues revealed that NOK is co-located with Akt and GSK-3β. Further study in NSCLC cell lines revealed that NOK overexpression can activate the AKT/GSK3β pathway. Conversely, knockdown of NOK can suppress the AKT/GSK3β pathway.Conclusion: Our results suggest that NOK overexpression correlated significantly with lymphatic metastasis, advanced pN and clinical stage in NSCLC. And NOK may promote EMT by activating the AKT/GSK3β/N-cadherin pathway in NSCLC.Keywords: NOK/STYK1, epithelial-mesenchymal transition, Akt, GSK3β, N-cadherin, non-small cell lung cancer
