Suwei Dong, Liang Zeng, Zhimin Liu, Ruilei Li, Yingying Zou, Zhen Li, Chunlei Ge, Zhangchao Lai, Yuanbo Xue, Jinyan Yang, Gaofeng Li, Xin Song
Cancer Research Institute of Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, People's Republic of China.
J Hematol Oncol. 2015 Oct 26;8:120. doi: 10.1186/s13045-015-0203-8.
Nemo-like kinase (NLK) is an evolutionarily conserved serine/threonine kinase that regulates the activity of a wide range of signal transduction pathways. Metformin, an oral antidiabetic drug, is used for cancer prevention. However, the significance and underlying mechanism of NLK and metformin in oncogenesis has not been fully elucidated. Here, we investigate a novel role of NLK and metformin in human non-small cell lung cancer (NSCLC).
NLK expression was analyzed in 121 NSCLCs and 92 normal lung tissue samples from benign pulmonary disease. Lentivirus vectors with NLK-shRNA were used to examine the effect of NLK on cell proliferation and tumorigenesis in vitro. Then, tumor xenograft mouse models revealed that NLK knockdown cells had a reduced ability for tumor formation compared with the control group in vivo. Multiple cell cycle regulator expression patterns induced by NLK silencing were examined by western blots in A549 cells. We also employed metformin to study its anti-cancer effects and mechanisms. Cancer stem cell property was checked by tumor sphere formation and markers including CD133, Nanog, c-Myc, and KLF4.
Immunohistochemical (IHC) analysis revealed that NLK expression was up-regulated in NSCLC cases (p < 0.001) and correlated with tumor T stage (p < 0.05). Silencing of NLK suppressed cell proliferation and tumorigenicity significantly in vitro and in vivo, which might be modulated by JUN family proteins. Furthermore, metformin selectively inhibits NLK expression and proliferation in NSCLC cells, but not immortalized noncancerous lung bronchial epithelial cells. In addition, both NLK knockdown and metformin treatment reduced the tumor sphere formation capacity and percentage of CD133+ cells. Accordingly, the expression level of stem cell markers (Nanog, c-Myc, and KLF4) were decreased significantly [corrected].
NLK is critical for cancer cell cycle progression, and tumorigenesis in NSCLC, NLK knockdown, and metformin treatment inhibit cancer cell proliferation and stemness. Metformin inhibits NLK expression and might be a potential treatment strategy for NSCLC.
Nemo样激酶（NLK）是一种进化上保守的丝氨酸/苏氨酸激酶，可调节多种信号转导途径的活性。二甲双胍是一种口服抗糖尿病药物，可用于癌症预防。然而，NLK和二甲双胍在肿瘤发生中的意义和潜在机制尚未完全阐明。在此，我们研究NLK和二甲双胍在人类非小细胞肺癌（NSCLC）中的新作用。
分析了121例NSCLC和92例来自良性肺部疾病的正常肺组织样本中NLK的表达。使用携带NLK-shRNA的慢病毒载体在体外检测NLK对细胞增殖和肿瘤发生的影响。然后，肿瘤异种移植小鼠模型显示，与对照组相比，体内敲低NLK的细胞形成肿瘤的能力降低。通过蛋白质免疫印迹法检测A549细胞中NLK沉默诱导的多种细胞周期调节因子的表达模式。我们还使用二甲双胍来研究其抗癌作用和机制。通过肿瘤球形成以及包括CD133、Nanog、c-Myc和KLF4在内的标志物来检测癌症干细胞特性。
免疫组织化学（IHC）分析显示，NSCLC病例中NLK表达上调（p < 0.001），且与肿瘤T分期相关（p < 0.05）。在体外和体内，NLK沉默均显著抑制细胞增殖和致瘤性，这可能由JUN家族蛋白调节。此外，二甲双胍选择性抑制NSCLC细胞中NLK的表达和增殖，但对永生化的非癌性肺支气管上皮细胞无此作用。此外，NLK敲低和二甲双胍处理均降低了肿瘤球形成能力和CD133 +细胞的百分比。因此，干细胞标志物（Nanog、c-Myc和KLF4）的表达水平显著降低[校正后]。
NLK对NSCLC中的癌细胞周期进展和肿瘤发生至关重要，敲低NLK和二甲双胍治疗可抑制癌细胞增殖和干性。二甲双胍抑制NLK表达，可能是NSCLC的一种潜在治疗策略。
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