Expression and significance of Traf-2 and Nck-interacting kinase in gastric cancer tissues_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Haichao ¹ , BAI Minghui ¹ , SU Baowei ¹ , LIU Shaopeng ¹ ,  JIANG Zhen ²

1. Department of General Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, P. R. China;
2. Department of Gastroenterology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471000,P. R. China;

Corresponding author：

JIANG Zhen, Email: jz211104@163.com

Keywords：

gastric cancer; Traf-2 and Nck-interacting protein kinase; prognosis

DOI：

10.7507/1007-9424.201906081

Video：

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Objective To investigate the expression level and the clinical significance of Traf-2 and Nck-interacting protein kinase (TNIK) in gastric cancer tissues.Methods We retrospectively collected 78 cases of gastric cancer and its adjacent tissues which were diagnosed by surgery and pathology, all the patients received surgery in the Department of General Surgery in Luoyang Central Hospital Affiliated to Zhengzhou University, from July 2014 to December 2017, as well as 42 cases of gastric ulcer tissues in the same period. The expression of TNIK protein was detected by using immunohistochemical method and Western blot method in 78 cases of human gastric cancer tissues, corresponding adjacent normal tissues, and 42 cases of gastric ulcer tissues, the relationship between expression of TNIK protein and clinicopathologial features of gastric cancer was explored.Results The positive expression rate of TNIK protein in gastric cancer tissues was 66.67% (52/78), and adjacent cancer tissues showed low expression rate of 11.54% (9/78), while it was 21.43% (9/42) in gastric ulcer tissues. On the positive expression rate of TNIK protein, gastric cancer tissues compared with adjacent cancer tissues and gastric ulcer tissues, the difference was statistically significant (P<0.05), however, there was no statistically significant difference between adjacent cancer tissues and gastric ulcer tissues (P>0.05). Western blot method showed that the expression level of TNIK protein in gastric cancer tissues was all significantly higher than that in adjacent cancer tissues and gastric ulcer tissues, the differences were statistically significant (P<0.05), but the difference was not significant when compared the adjacent cancer tissues and gastric ulcer tissues (P=0.772). The expression of TNIK protein was irrelevent to sexual distinction, CEA value, tumor diameter, and pathological type (P>0.05), while it was closely related to patients’ age, TNM stage, differentiation grade, distant metastasis, and lymph node metastasis (P<0.05). The prognosis of patients with positive expression of TNIK protein was worse than that of patients with negative expression of TNIK protein (P<0.05).Conclusion TNIK protein is highly expressed in gastric cancer tissues, which is associated with poorly prognostic factors and poor prognosis, and it may be a therapeutic target in patients with gastric cancer.

Citation： LIU Haichao, BAI Minghui, SU Baowei, LIU Shaopeng, JIANG Zhen. Expression and significance of Traf-2 and Nck-interacting kinase in gastric cancer tissues. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(3): 320-325. doi: 10.7507/1007-9424.201906081 Copy

1.	冯丽萍, 余盈, 李跃. LncRNA RAB11B-AS1在胃癌组织中的表达及临床意义. 临床肿瘤学杂志, 2017, 22(7): 592-596.
2.	黎军和, 熊建萍. 胃癌分子靶向治疗研究新进展. 中国肿瘤临床, 2015, 42(23): 1118-1123.
3.	Shitashige M, Satow R, Jigami T, et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res, 2010, 70(12): 5024-5033.
4.	Yu DH, Zhang X, Wang H, et al. The essential role of TNIK gene amplification in gastric cancer growth. Oncogenesis, 2014, 2: e89.
5.	张淦梅. 肿瘤病理诊断中特殊染色联合免疫组化技术的应用效果及检测阳性率评价. 临床检验杂志(电子版), 2019, 8(4): 262-263 .
6.	夏虹, 张久丹, 吕杭丽, 等. 抗 1 型血小板反应蛋白7A抗体与特发性膜性肾病的关系. 中国现代医生, 2017, 55(15): 19-22, 26.
7.	李浩淼, 孙海波, 郑燕, 等. AJCC/UICC第八版食管及食管胃交界部癌TNM分期解读及中文版主要内容. 中国胸心血管外科临床杂志, 2017, 24(2): 87-92.
8.	赵晓阳. 家族性胃癌与散发性胃癌的临床特点及预后. 临床医药文献电子杂志, 2019, 6(10): 90.
9.	胡敏, 赵廷宽, 刘静, 等. LKB1低表达与胃癌肿瘤血管形成的关系及其临床意义. 中华病理学杂志, 2019, 48(1): 42-44.
10.	Masuda M, Uno Y, Ohbayashi N, et al. TNIK inhibition abrogates colorectal cancer stemness. Nat Commun, 2016, 7: 12586.
11.	Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther, 2015, 156: 1-9.
12.	Sun Y, Gao X, Wu P, et al. Jatrorrhizine inhibits mammary carcinoma cells by targeting TNIK mediated Wnt/β-catenin signalling and epithelial-mesenchymal transition (EMT). Phytomedicine, 2019, 63: 153015.
13.	Chen X, Shibata AC, Hendi A, et al. Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans. Elife, 2018, 7: e38801.
14.	Zhou X, Wang L, Xiao W, et al. Memantine improves cognitive function and alters hippocampal and cortical proteome in triple transgenic mouse model of Alzheimer’s disease. Exp Neurobiol, 2019, 28(3): 390-403.
15.	王建刚, 石玉秀. Metformin对PTSD大鼠海马神经元AMPK通路的作用及其保护机制的研究. 沈阳: 中国医科大学, 2017.
16.	Lee RS, Zhang L, Berger A, et al. Characterization of the ERG-regulated kinome in prostate cancer identifies TNIK as a potential therapeutic target. Neoplasia, 2019, 21(4): 389-400.
17.	Larhammar M, Huntwork-Rodriguez S, Rudhard Y, et al. The Ste20 family kinases MAP4K4, MINK1, and TNIK converge to regulate stress-induced JNK signaling in neurons. J Neurosci, 2017, 37(46): 11074-11084.
18.	Read J, Collie IT, Nguyen-McCarty M, et al. Tool inhibitors and assays to interrogate the biology of the TRAF2 and NCK interacting kinase. Bioorg Med Chem Lett, 2019, 29(15): 1962-1967 .
19.	Lee Y, Jung JI, Park KY, et al. Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells. Oncotarget, 2017, 8(25): 41091-41101.
20.	Chon HJ, Lee Y, Bae KJ, et al. Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells. Amino Acids, 2016, 48(7): 1591-1599.
21.	吴平平. 药根碱靶向肿瘤蛋白TNIK抑制乳腺癌生长转移机制研究. 杭州: 浙江理工大学, 2018.
22.	严锦, 崔世维, 刘艳梅. TNIK通过炎症机制参与肝脏胰岛素抵抗. 南通大学学报: 医学版, 2017, 37(3): 253-257.
23.	刘艳凤, 苗梦媛, 毛伟征. 胃癌发病分子机制及靶向治疗研究新进展. 解放军预防医学杂志, 2019, 37(4): 189-190.
24.	Masuda M, Yamada T. The emergence of TNIK as a therapeutic target for colorectal cancer. Expert Opin Ther Targets, 2017, 21(4): 353-355.
25.	Guo Y, Liu N, Liu K, et al. Capsaicin inhibits migration and invasion via the AMPK/NF-kB signaling pathway in esophagus sequamous cell carcinoma a by decreasing matrix metallo-proteinase-9 expression. Biosci Rep, 2019, 39(8): 19.
26.	Yuan G, Rong L, Liu J, et al. Serum derived hepatitis C virus can infect human glioblastoma cell line SF268 and activate the PI3K Akt pathway. Mol Med Rep, 2019, 19(5): 4441-4448.
27.	Fabric HS, Eduardo OF, Carla DDS, et al. Prognostic and predictive markers in breast cancer: issues related to molecular determinants of outcome. Breast J, 2015, 4(5): 379-382.
28.	Wiggins M, Sherman J, Pierson S. The medico-legal and ethical considerations associated with intraoperative neurophysiological monitoring in the USA: overview and proposed guidelines for legal and risk management professionals. International J Liability and Scientific Enquiry, 2013, 6(1/2/3): 42.
29.	Yamada T, Masuda M. Emergence of TNIK inhibitors in cancer therapeutics. Cancer Sci, 2017, 108(5): 818-823.
30.	Tan Z, Chen L, Zhang S. Comprehensive modeling and discovery of mebendazole as a novel TRAF2- and NCK-interacting kinase inhibitor. Sci Rep, 2016, 21(6): 33534.
31.	Takahashi H, Ishikawa T, Ishiguro M, et al. Prognostic significance of Traf2- and Nck- interacting kinase (TNIK) in colorectal cancer. BMC Cancer, 2015, 15(1): 794.
32.	Zhang Y, Jiang H, Qin M, et al. TNIK serves as a novel biomarker associated with poor prognosis in patients with pancreatic cancer. Tumour Biol, 2016, 37(1): 1035-1040.
33.	Liang JJ, Wang H, Rashid A, et al. Expression of MAP4K4 is associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Clin Cancer Res, 2008, 14(21): 7043-7049.
34.	Wang Q, Amato SP, Rubitski DM, et al. Identification of phosphorylation consensus sequences and endogenous neuronal substrates of the psychiatric risk kinase TNIK. J Pharmacol Exp Ther, 2016, 356(2): 410-423.
35.	张勇. TNIK在胰腺癌中的表达及生物学意义. 天津: 天津医科大学, 2014.
36.	Yu DH, Zhang X, Wang H, et al. The essential role of TNIK gene amplification in gastric cancer growth. Oncogenesis, 2014, 3: e93.

1. 冯丽萍, 余盈, 李跃. LncRNA RAB11B-AS1在胃癌组织中的表达及临床意义. 临床肿瘤学杂志, 2017, 22(7): 592-596.
2. 黎军和, 熊建萍. 胃癌分子靶向治疗研究新进展. 中国肿瘤临床, 2015, 42(23): 1118-1123.
3. Shitashige M, Satow R, Jigami T, et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res, 2010, 70(12): 5024-5033.
4. Yu DH, Zhang X, Wang H, et al. The essential role of TNIK gene amplification in gastric cancer growth. Oncogenesis, 2014, 2: e89.
5. 张淦梅. 肿瘤病理诊断中特殊染色联合免疫组化技术的应用效果及检测阳性率评价. 临床检验杂志(电子版), 2019, 8(4): 262-263 .
6. 夏虹, 张久丹, 吕杭丽, 等. 抗 1 型血小板反应蛋白7A抗体与特发性膜性肾病的关系. 中国现代医生, 2017, 55(15): 19-22, 26.
7. 李浩淼, 孙海波, 郑燕, 等. AJCC/UICC第八版食管及食管胃交界部癌TNM分期解读及中文版主要内容. 中国胸心血管外科临床杂志, 2017, 24(2): 87-92.
8. 赵晓阳. 家族性胃癌与散发性胃癌的临床特点及预后. 临床医药文献电子杂志, 2019, 6(10): 90.
9. 胡敏, 赵廷宽, 刘静, 等. LKB1低表达与胃癌肿瘤血管形成的关系及其临床意义. 中华病理学杂志, 2019, 48(1): 42-44.
10. Masuda M, Uno Y, Ohbayashi N, et al. TNIK inhibition abrogates colorectal cancer stemness. Nat Commun, 2016, 7: 12586.
11. Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther, 2015, 156: 1-9.
12. Sun Y, Gao X, Wu P, et al. Jatrorrhizine inhibits mammary carcinoma cells by targeting TNIK mediated Wnt/β-catenin signalling and epithelial-mesenchymal transition (EMT). Phytomedicine, 2019, 63: 153015.
13. Chen X, Shibata AC, Hendi A, et al. Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans. Elife, 2018, 7: e38801.
14. Zhou X, Wang L, Xiao W, et al. Memantine improves cognitive function and alters hippocampal and cortical proteome in triple transgenic mouse model of Alzheimer’s disease. Exp Neurobiol, 2019, 28(3): 390-403.
15. 王建刚, 石玉秀. Metformin对PTSD大鼠海马神经元AMPK通路的作用及其保护机制的研究. 沈阳: 中国医科大学, 2017.
16. Lee RS, Zhang L, Berger A, et al. Characterization of the ERG-regulated kinome in prostate cancer identifies TNIK as a potential therapeutic target. Neoplasia, 2019, 21(4): 389-400.
17. Larhammar M, Huntwork-Rodriguez S, Rudhard Y, et al. The Ste20 family kinases MAP4K4, MINK1, and TNIK converge to regulate stress-induced JNK signaling in neurons. J Neurosci, 2017, 37(46): 11074-11084.
18. Read J, Collie IT, Nguyen-McCarty M, et al. Tool inhibitors and assays to interrogate the biology of the TRAF2 and NCK interacting kinase. Bioorg Med Chem Lett, 2019, 29(15): 1962-1967 .
19. Lee Y, Jung JI, Park KY, et al. Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells. Oncotarget, 2017, 8(25): 41091-41101.
20. Chon HJ, Lee Y, Bae KJ, et al. Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells. Amino Acids, 2016, 48(7): 1591-1599.
21. 吴平平. 药根碱靶向肿瘤蛋白TNIK抑制乳腺癌生长转移机制研究. 杭州: 浙江理工大学, 2018.
22. 严锦, 崔世维, 刘艳梅. TNIK通过炎症机制参与肝脏胰岛素抵抗. 南通大学学报: 医学版, 2017, 37(3): 253-257.
23. 刘艳凤, 苗梦媛, 毛伟征. 胃癌发病分子机制及靶向治疗研究新进展. 解放军预防医学杂志, 2019, 37(4): 189-190.
24. Masuda M, Yamada T. The emergence of TNIK as a therapeutic target for colorectal cancer. Expert Opin Ther Targets, 2017, 21(4): 353-355.
25. Guo Y, Liu N, Liu K, et al. Capsaicin inhibits migration and invasion via the AMPK/NF-kB signaling pathway in esophagus sequamous cell carcinoma a by decreasing matrix metallo-proteinase-9 expression. Biosci Rep, 2019, 39(8): 19.
26. Yuan G, Rong L, Liu J, et al. Serum derived hepatitis C virus can infect human glioblastoma cell line SF268 and activate the PI3K Akt pathway. Mol Med Rep, 2019, 19(5): 4441-4448.
27. Fabric HS, Eduardo OF, Carla DDS, et al. Prognostic and predictive markers in breast cancer: issues related to molecular determinants of outcome. Breast J, 2015, 4(5): 379-382.
28. Wiggins M, Sherman J, Pierson S. The medico-legal and ethical considerations associated with intraoperative neurophysiological monitoring in the USA: overview and proposed guidelines for legal and risk management professionals. International J Liability and Scientific Enquiry, 2013, 6(1/2/3): 42.
29. Yamada T, Masuda M. Emergence of TNIK inhibitors in cancer therapeutics. Cancer Sci, 2017, 108(5): 818-823.
30. Tan Z, Chen L, Zhang S. Comprehensive modeling and discovery of mebendazole as a novel TRAF2- and NCK-interacting kinase inhibitor. Sci Rep, 2016, 21(6): 33534.
31. Takahashi H, Ishikawa T, Ishiguro M, et al. Prognostic significance of Traf2- and Nck- interacting kinase (TNIK) in colorectal cancer. BMC Cancer, 2015, 15(1): 794.
32. Zhang Y, Jiang H, Qin M, et al. TNIK serves as a novel biomarker associated with poor prognosis in patients with pancreatic cancer. Tumour Biol, 2016, 37(1): 1035-1040.
33. Liang JJ, Wang H, Rashid A, et al. Expression of MAP4K4 is associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Clin Cancer Res, 2008, 14(21): 7043-7049.
34. Wang Q, Amato SP, Rubitski DM, et al. Identification of phosphorylation consensus sequences and endogenous neuronal substrates of the psychiatric risk kinase TNIK. J Pharmacol Exp Ther, 2016, 356(2): 410-423.
35. 张勇. TNIK在胰腺癌中的表达及生物学意义. 天津: 天津医科大学, 2014.
36. Yu DH, Zhang X, Wang H, et al. The essential role of TNIK gene amplification in gastric cancer growth. Oncogenesis, 2014, 3: e93.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expression and significance of Traf-2 and Nck-interacting kinase in gastric cancer tissues

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