NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin

Journal of Hematology & Oncology

Song Xin⁴  Li Gaofeng¹  Yang Jinyan⁴  Xue Yuanbo⁴  Lai Zhangchao⁴  Ge Chunlei⁴  Li Zhen⁴  Zou Yingying²  Li Ruilei⁴  Liu Zhimin⁴  Zeng Liang³  Dong Suwei⁴ 

[1] Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, Yunnan, People’s Republic of China;Department of Pathology and Pathophysiology, Kunming Medical University, Kunming, Yunnan, People’s Republic of China;Department of Pathology, Hunan Tumor Hospital, Changsha, Hunan, 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

关键词: Stemness;    Metformin;    Proliferation;    NSCLC;    NLK;   

Others  :  1233271
DOI  :  10.1186/s13045-015-0203-8

 received in 2015-05-13, accepted in 2015-09-28,  发布年份 2015

【 摘 要 】

Objective

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).

Materials and methods

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 TLF4.

Results

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 TLF4) were decreased significantly.

Conclusion

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.

【 授权许可】

   
2015 Suwei et al.

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