摘要
背景：Nemo样激酶（NLK）是一种进化上保守的MAP激酶相关激酶，参与几种人类癌症的发病机制。 目的：本研究旨在探讨NLK在肺癌中的表达及作用及其机制。 方法：我们通过蛋白质印迹分析检测了肺癌组织中NLK的表达。 我们分别通过基因转染或RNA干扰增强或敲低了肺癌细胞中的NLK表达，并检测了Wnt信号通路和上皮 - 间质转化（EMT）中关键蛋白的表达改变。 我们还通过细胞增殖，集落形成和基质胶侵袭测定检查了NLK在肺癌细胞增殖和侵袭中的作用。 结果：发现肺癌组织样品中的NLK表达显着高于相应的健康肺组织样品。 NLK的过度表达与肺癌患者的预后不良相关。 NLK的过表达上调β-连环蛋白，TCF4和Wnt靶基因，例如细胞周期蛋白D1，c-Myc和MMP7。 N-cadherin和TWIST是EMT中的关键蛋白，被上调，而E-钙粘蛋白表达减少。 另外，在NLK过表达细胞中，增殖，集落形成和入侵被证实是增强的。 在NLK敲低肺癌细胞后，我们获得了相反的结果。 结论：NLK在肺癌中过度表达，预示着预后不良。 NLK的过表达激活Wnt信号传导途径和EMT并促进肺癌细胞的增殖和侵袭。
关键词: Nemo样激酶，肺癌，wnt信号通路，上皮 - 间质转化，增殖，侵袭。
图形摘要
[2]
Chen, W.; Zheng, R.; Zeng, H.; Zhang, S.; He, J. Annual report on status of cancer in China, 2011. Chin. J. Cancer Res., 2015, 27(1), 2-12.
[3]
Larsen, J.E.; Minna, J.D. Molecular biology of lung cancer: Clinical implications. Clin. Chest Med., 2011, 32(4), 703-740.
[4]
Jones, C.M.; Brunelli, A.; Callister, M.E.; Franks, K.N. Multimodality treatment of advanced non-small cell lung cancer: Where are we with the Evidence? Curr. Surg. Rep., 2018, 6(2), 5.
[5]
Wang, L.Y.; Cui, J.J.; Guo, A.X.; Yin, J.Y. Clinical efficacy and safety of afatinib in the treatment of non-small-cell lung cancer in Chinese patients. OncoTargets Ther., 2018, 11, 529-538.
[6]
Brott, B.K.; Pinsky, B.A.; Erikson, R.L. Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus. Proc. Natl. Acad. Sci. USA, 1998, 95(3), 963-968.
[7]
Ishitani, T.; Ishitani, S. Nemo-like kinase, a multifaceted cell signaling regulator. Cell. Signal., 2013, 25(1), 190-197.
[8]
Huang, Y.; Yang, Y.; He, Y.; Li, J. The emerging role of Nemo-like kinase (NLK) in the regulation of cancers. Tumour Biol., 2015, 36(12), 9147-9152.
[9]
Emami, K.H.; Brown, L.G.; Pitts, T.E.; Sun, X.; Vessella, R.L.; Corey, E. Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells. The Prostate, 2009, 69(14), 1481-1492.
[10]
Cui, G.; Li, Z.; Shao, B.; Zhao, L.; Zhou, Y.; Lu, T.; Wang, J.; Shi, X.; Wang, J.; Zuo, G.; Zhu, W.; Shen, A. Clinical and biological significance of nemo-like kinase expression in glioma. J. Clin. Neurosci., 2011, 18(2), 271-275.
[11]
Huang, Y.; Jiang, Y.; Lu, W.; Zhang, Y. Nemo-like kinase associated with proliferation and apoptosis by c-Myb degradation in breast cancer. PLoS One, 2013, 8(7), e69148.
[12]
Chen, S.; Ma, Z.; Chen, X.; Zhang, J. Prognostic significance of nemo-like kinase in nasopharyngeal carcinoma. Mol. Med. Rep., 2014, 10(1), 131-136.
[13]
Yang, W.; Gu, L.; Yang, C.; Liu, T. Expression of Nemo-like kinase in cervical squamous cell carcinoma: a clinicopathological study. OncoTargets Ther., 2018, 11, 743-749.
[14]
Zhang, W.; He, J.; Du, Y.; Gao, X.H.; Liu, Y.; Liu, Q.Z.; Chang, W.J.; Cao, G.W.; Fu, C.G. Upregulation of nemo-like kinase is an independent prognostic factor in colorectal cancer. World J. Gastroenterol., 2015, 21(29), 8836-8847.
[15]
Tan, Z.; Li, M.; Wu, W.; Zhang, L.; Ding, Q.; Wu, X.; Mu, J.; Liu, Y. NLK is a key regulator of proliferation and migration in gallbladder carcinoma cells. Mol. Cell. Biochem., 2012, 369(1-2), 27-33.
[16]
Lv, M.; Li, Y.; Tian, X.; Dai, S.; Sun, J.; Jin, G.; Jiang, S. Lentivirus-mediated knockdown of NLK inhibits small-cell lung cancer growth and metastasis. Drug Des. Devel. Ther., 2016, 10, 3737-3746.
[17]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72, 248-254.
[18]
Wang, Y.; Lei, L.; Zheng, Y.W.; Zhang, L.; Li, Z.H.; Shen, H.Y.; Jiang, G.Y.; Zhang, X.P.; Wang, E.H.; Xu, H.T. Odd-skipped related 1 inhibits lung cancer proliferation and invasion by reducing Wnt signaling through the suppression of SOX9 and beta-catenin. Cancer Sci., 2018, 109(6), 1799-1810.
[19]
Han, Q.; Kremerskothen, J.; Lin, X.; Zhang, X.; Rong, X.; Zhang, D.; Wang, E. WWC3 inhibits epithelial-mesenchymal transition of lung cancer by activating Hippo-YAP signaling. OncoTargets Ther., 2018, 11, 2581-2591.
[20]
Lanczky, A.; Nagy, A.; Bottai, G.; Munkacsy, G.; Szabo, A.; Santarpia, L.; Gyorffy, B. miRpower: A web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients. Breast Cancer Res. Treat., 2016, 160(3), 439-446.
[21]
Suwei, D.; Liang, Z.; Zhimin, L.; Ruilei, L.; Yingying, Z.; Zhen, L.; Chunlei, G.; Zhangchao, L.; Yuanbo, X.; Jinyan, Y.; Gaofeng, L.; Xin, S. NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin. J. Hematol. Oncol., 2015, 8, 120.
[22]
Lv, L.; Wan, C.; Chen, B.; Li, M.; Liu, Y.; Ni, T.; Yang, Y.; Liu, Y.; Cong, X.; Mao, G.; Xue, Q. Nemo-like kinase (NLK) inhibits the progression of NSCLC via negatively modulating WNT signaling pathway. J. Cell. Biochem., 2014, 115(1), 81-92.
[23]
Zhang, X.W.; Chen, S.Y.; Xue, D.W.; Xu, H.H.; Yang, L.H.; Xu, H.T.; Wang, E.H. Expression of Nemo-like kinase was increased and negatively correlated with the expression of TCF4 in lung cancers. Int. J. Clin. Exp. Pathol., 2015, 8(11), 15086-15092.
[24]
Zuccarini, M.; Giuliani, P.; Ziberi, S.; Carluccio, M.; Iorio, P.D.; Caciagli, F.; Ciccarelli, R. The Role of Wnt signal in glioblastoma development and progression: a possible new pharmacological target for the therapy of this tumor. Genes , 2018, 9(2)
[25]
Jamieson, C.; Sharma, M.; Henderson, B.R. Targeting the beta-catenin nuclear transport pathway in cancer. Semin. Cancer Biol., 2014, 27, 20-29.
[26]
John, R.R.; Malathi, N.; Ravindran, C.; Anandan, S. Mini review: Multifaceted role played by cyclin D1 in tumor behavior. Indian J. Dent. Res., 2017, 28(2), 187-192.
[27]
Banday, M.Z.; Sameer, A.S.; Mir, A.H.; Mokhdomi, T.A.; Chowdri, N.A.; Haq, E. Matrix metalloproteinase (MMP) -2, -7 and -9 promoter polymorphisms in colorectal cancer in ethnic Kashmiri population - A case-control study and a mini review. Gene, 2016, 589(1), 81-89.
[28]
Ishitani, T.; Ninomiya-Tsuji, J.; Matsumoto, K. Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Mol. Cell. Biol., 2003, 23(4), 1379-1389.
[29]
Ota, S.; Ishitani, S.; Shimizu, N.; Matsumoto, K.; Itoh, M.; Ishitani, T. NLK positively regulates Wnt/beta-catenin signalling by phosphorylating LEF1 in neural progenitor cells. EMBO J., 2012, 31(8), 1904-1915.
[30]
Hotz, B.; Arndt, M.; Dullat, S.; Bhargava, S.; Buhr, H.J.; Hotz, H.G. Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin. Cancer Res., 2007, 13(16), 4769-4776.
Related Books
Frontiers in Clinical Drug Research - Anti-Cancer Agents
NEOPLASIA and FERTILITY
Breast Cancer: Current Trends in Molecular Research
The Evolution of Radionanotargeting towards Clinical Precision Oncology: A Festschrift in Honor of Kalevi Kairemo
Nanotherapeutics for the Treatment of Hepatocellular Carcinoma
Topics in Anti-Cancer Research
Frontiers in Clinical Drug Research - Anti-Cancer Agents
Modern Cancer Therapies and Traditional Medicine: An Integrative Approach to Combat Cancers
Herbal Medicine: Back to the Future
Thrombosis in Cancer: A Medical Professional's Guide to Cancer Associated Thrombosis
Article Metrics
62
6