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Effect of NELL1 on Lung Cancer Stem‑Like Cell Differentiation

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Effect of NELL1 on Lung Cancer Stem‑Like Cell Differentiation ONCOLOGY REPORTS 41: 1817-1826, 2019 Effect of NELL1 on lung cancer stem‑like cell differentiation YUANFEN ZHAI1-3, RONGBIN WEI8, SHUANG SHA1,7, CHENGZHAO LIN1, HEYONG WANG4, XINQUAN JIANG5,6 and GENTAO LIU1-3 1Center for Translational Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433; 2Shanghai Ultra-T Immunotherapeutics Co., Ltd., Shanghai Biomed-Union Biotechnology Co., Ltd., Shanghai International Medical Zone, Shanghai 201321; 3Department of Oncology, Shanghai Oriental Hospital, Tongji University School of Medicine, Shanghai 200120; 4The Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433; 5Department of Prosthodontics, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200011; 6Oral Bioengineering and Regenerative Medicine Lab, Shanghai Research Institute of Stomatology, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai 200011; 7Clinical Research Center, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201800; 8State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southest University, Nanjing, Jiangsu 210009, P.R. China Received July 3, 2018; Accepted November 29, 2018 DOI: 10.3892/or.2019.6954 Abstract. The cancer stem cell theory recently has received agar colony formation and cell invasion assay. In addition, enormous attention in cancer biology. Lung cancer stem-like as determined by cell proliferation assay, overexpression of cells are a subpopulation of undifferentiated lung tumor cells NELL1 increased the chemotherapeutic sensitivity of 95-D critical for lung cancer tumorigenesis, metastasis and resis- LCSCs to carboplatin and cisplatin. NELL1 also reduced the tance to therapy and disease relapse. The neural EGFL like 1 expression of phospho-MET (p-MET), Notch3 and HES1, (NELL1) is a potent growth factor believed to preferentially which suggests that NELL1 may induce 95-D LCSC differen- target cells committed to the osteochondral lineage; yet, its tiation by inhibiting the expression of c-MET-Notch signaling. expression and function in lung cancer are largely unknown. Our results suggest that NELL1 induces lung cancer stem-like In the present study, we used specific medium to accumu- cell differentiation, which provides a new potential therapeutic late lung cancer stem-like cells of 95-D cells in spheres and target for cancer stem cells. obtained these highly expressed CD133 cells through flow cytometric cell sorting of CD133-stained cells which were Introduction termed 95-D lung cancer stem-like cells (95-D LCSCs). These 95-D LCSCs highly expressed stemness genes CD133, Oct4 Lung cancer is the leading cause of cancer-related death world- and Sox2 determined by western blot analysis and quantitative wide (1). It includes two major types: Small cell lung cancer real-time polymerase chain reaction (qPCR) analysis. Notably, (SCLC) and non-small cell lung cancer (NSCLC). Although we found that overexpression of NELL1 significantly reduced some lung cancer tumors are resectable or initially responsive colony formation and invasion of 95-D LCSCs tested by soft to traditional therapies, drug resistance and poor prognosis remain high, leading to a poor 5-year survival rate of less than 15% (2-5). Approximately, non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases (6). Traditional and progressive treatments have been applied clinically, including Correspondence to: Dr Xinquan Jiang, Department of Prostho- dontics, Ninth People's Hospital Affiliated to Shanghai Jiao Tong chemotherapy, radiotherapy and biotherapy, but the resistance University, School of Medicine, 639 Zhizaoju Road, Shanghai 200011, to radiotherapy and chemotherapy remains a critical issue P. R. Ch i na for lung cancer therapy (7,8). Recently, it has been suggested E-mail: [email protected] that a subpopulation termed cancer stem cells (CSCs) cause initiation, drug resistance, metastasis and recurrence of cancer Dr Gentao Liu, Shanghai Ultra-T Immunotherapeutics Co., Ltd., Shanghai Biomed-Union Biotechnology Co., Ltd., Shanghai Interna- cells. CSCs are divided asymmetrically to stem cells that tional Medical Zone, 908 Ziping Road, Shanghai 201321, P.R. China have the capacity of self-renewal, and the other cells that will E-mail: [email protected]; [email protected] differentiate and produce phenotypically diverse tumor-consti- tutive cancer cells (9). Researchers first reported CSCs in Key words: lung cancer stem-like cells, 95-D cells, NELL1, p-MET, leukemia (10), and subsequently in solid tumors, such as colon, Notch3 brain, breast and lung cancer (11-14). A small subpopulation of lung cancer cells called cancer stem-like cells (CSCs) have 1818 ZHAI et al: EFFECT OF NELL1 ON LUNG CANCER STEM-LIKE CELL DIFFERENTIATION been certified in many studies using different isolation assays, adenocarcinoma and normal counterparts was analyzed using including accumulation in specific medium and cell sorting the Oncomine database by searching ‘Gene:NELL1’; ‘Analysis by certain markers such as CD133+ (15-18). Human 95-D cells Type: Cancer vs. normal analysis’; ‘Cancer Type: Lung cancer’. are highly invasive and metastatic lung cancer cells (19). In previous research, cultured in specific medium, 95‑D cells Sphere formation. The 95-D LCSCs were accumulated by can be used to accumulated lung cancer stem cells in spheres, sphere formation. Basically, the 95-D cells were digested into which were called LCSCs (20). Conventional and traditional single cells with 0.25% trypsin and washed with phosphate- therapies that fail to eradicate CSCs may reduce tumor cells buffered saline (PBS). The cells were seeded in ultra-low temporarily; however, resistance, metastasis and relapse are attachment dishes and cultured in neuroblast medium with more likely to occur when treatment is suspended. After the 20 ng/ml bFGF, 20 ng/ml EGF and B27 for 7 days to form discovery of cancer stem cells, efficient approaches targeting spheres. The spheres were centrifuged and digested into single CSCs is considered to be indispensable for eradicating cancer cells for further studies. cells (21). Neural EGFL like 1 (NELL1) was originally cloned from Flow cytometry. To analyze the CD133 relative expression a human fetal-brain cDNA library (22). Previous research in the accumulated LCSCs in spheres, cells were harvested has found that NELL1 plays an important role in osteogenic and washed with FACS buffer [PBS containing FBS (1%; differentiation (23). NELL1 is highly expressed in patients Sigma-Aldrich; Merck KGaA, Darmstadt, Germany)] and with craniosynostosis, and NELL1 can induce bone regenera- sodium azide (0.05%; Sigma-Aldrich; Merck KGaA). The tion in calvarial defects (24). Overexpression of NELL1 was CD133-PE/Cy7 (anti-human; dilution 1:100; cat. no. 372810; found to induce apoptosis in osteoblasts during craniofacial BioLegend, Shanghai, China) antibody diluted in FACS buffer development (25). On a cellular level, NELL1 is suggested to was added directly to this mixture and incubated for 30 min promote osteoblast differentiation. Thus, we aimed to ascer- at 4˚C in the dark. Meanwhile the IgG1‑PE/Cy7 (anti-human; tain whether NELL1 could induce CSC differentiation. In the dilution 1:100; cat. no. 401908; BioLegend) antibody was used present study, we investigated the effects of NELL1 on 95-D as a negative control. Cells were washed and resuspended in LCSCs. FACS buffer. The cells were maintained on ice until the anal- Moreover, expression of the NELL1 gene has been studied ysis using the FACSCalibur flow cytometer (BD Biosciences) in several types of cancer. In several cancers, NELL1 has and sorting using FACSAria flow cytometer (BD Biosciences). been found to be related with poor prognosis. In human renal Results were obtained by analyzing data with FlowJo version cell carcinoma, it was shown that NELL1 was significantly 7.6.1 software (FlowJo LLC, Ashland, OR, USA). The results downregulated in renal cell carcinoma, NELL1 gene was represent the mean value of three independent experiments. hypermethylation in renal cell carcinoma cell lines (26). The experiments were performed independently three times NELL1 was also found to be downregulated in esophageal and a representative is shown. squamous cell carcinoma (27). In glioblastoma cell lines, NELL1 is lowly expressed (28). However, little is known Plasmid and transfection. To prepare the NELL1 expression concerning the function of NELL1 in NSCLC. In the present construct, the NELL1 cDNA fragment (2932 bp, gene acces- study, we investigated the effects of NELL1 on lung cancer sion #BC069674.1) was amplified by PCR in vitro. The PCR stem-like cells. products were digested with NheI and SgsI restriction enzymes and inserted into corresponding sites of the PDS023_PL_IRES Materials and methods vector. The PDS023_PL_IRES lentivirus empty vector or vectors for NELL1 were co-transfected with lentivirus packing Cell culture and reagents. The human NSCLC 95-D cell vector pMDLg/pRRE, RSV-rev and pMD2.G into 293T cells line, which is a commercial cell line, was obtained from the to obtain lentiviral supernatant. The viral supernatant was Chinese Academy of Science (Shanghai, China). 95-D cells collected after 48 and 72 h. Wild-type early passage 95-D were cultured with Hyclone™ RPMI-1640 medium
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