Neuron-specific enolase promotes stem cell-like characteristics of small-cell lung cancer by downregulating NBL1 and activating the BMP2/Smad/ID1 pathway
Lin Lu,
Zhiqiang Zha,
Peiling Zhang,
Peipei Wang,
Xia Liu,
Xisheng Fang,
Chengyin Weng,
Baoxiu Li,
Haibo Mao,
Lina Wang,
Mingmei Guan,
Yong Wu,
Zhixiang Xu,
Zhongqiu Liu,
Guolong Liu
Affiliations
Lin Lu
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Zhiqiang Zha
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Peiling Zhang
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Peipei Wang
Department of Medical Oncology, Guangzhou First People’s Hospital, Guangzhou Medical University
Xia Liu
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Xisheng Fang
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Chengyin Weng
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Baoxiu Li
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Haibo Mao
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Lina Wang
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Mingmei Guan
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Yong Wu
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Zhixiang Xu
Division of Hematology and Oncology, Comprehensive Cancer Center, the University of Alabama at Birmingham
Zhongqiu Liu
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine
Guolong Liu
Department of Medical Oncology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology
Abstract Little is known about the biological functions of neuron-specific enolase (NSE) as a specific biomarker for small-cell lung cancer (SCLC). Herein, we elucidate the effect and mechanism of NSE on SCLC stem cell-like characteristics. Upregulated NSE expression was observed in spheroid cells. The gain-of-function and loss-of-function approaches demonstrated that modulation of NSE positively regulated cell proliferation, drug resistance, spherical clone formation, tumor growth, and stem cell-like characteristics of SCLC cells. Mechanistic studies revealed that NSE might downregulate the expression of neuroblastoma suppressor of tumorigenicity 1 (NBL1) by interacting with NBL1, thereby attenuating the competitive inhibitory effect of NBL1 on BMP2 and enhancing the interaction between BMP2 and BMPR1A; this, in turn, may activate the BMP2/Smad/ID1 pathway and promote SCLC stem cell-like characteristics. Moreover, overexpression of NBL1or knockdown of BMP2 rescued the NSE-induced stem cell-like characteristics. In clinical specimens, NSE expression was positively associated with ALDH1A1 expression and negatively correlated with NBL1 expression. High NSE and ALDH1A1 expressions and low NBL1 expression were correlated with poor prognosis in patients with SCLC. In summary, our study demonstrated that NSE promoted stem cell-like characteristics of SCLC via NBL1 and the activation of the BMP2/Smad/ID1 pathway.
