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Qiang Wang,1 Jinrong Liao,2 Zhiyong He,1,3 Ying Su,2 Dong Lin,1 Ling Xu,1 Haipeng Xu,1 Jinghui Lin1 1 Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou 350014, People’s Republic of China; 2Department of Radiobiology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou 350014, People’s Republic of China; 3Fujian Provincial Key Laboratory of Translation Cancer Medicine, Fuzhou 350014, People’s Republic of ChinaCorrespondence: Zhiyong HeDepartment of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, No. 420 Fuma Road, Fuzhou City, Fujian Province 350014, People’s Republic of ChinaEmail zhiyonghecn@sina.comBackground: miR-214 has been reported to contribute to erlotinib resistance in non-small-cell lung cancer (NSCLC) through targeting LHX6; however, the molecular mechanisms underlying the involvement of LHX6 in mediating the resistance to EGFR-TKIs in erlotinib-resistant NSCLC HCC827 (HCC827/ER) cells remain unknown. This study aimed to investigate the mechanisms responsible for the contribution of LHX6 to EGFR-TKIs resistance in HCC827/ER cells.Materials and Methods: HCC827/ER cells were generated by erlotinib treatment at a dose-escalation scheme. LHX6 knockout or overexpression was modeled in HCC827 and HCC827/ER cells, and then erlotinib IC50 values were measured. The cell migration ability was evaluated using a transwell migration assay, and the TCF/LEF luciferase activity was assessed with a TCF/LEF reporter luciferase assay. LHX6, β-catenin and Cyclin D1 expression was quantified using qPCR and Western blotting assays. In addition, the LHX6 expression was detected in lung cancer and peri-cancer specimens using immunohistochemical staining, and the associations of LHX expression with the clinicopathological characteristics of lung cancer were evaluated.Results: Lower LHX6 expression was detected in HCC827/ER cells than in HCC827 cells (P < 0.0001), while higher β-catenin expression was seen in HCC827/ER cells than in HCC827 cells (P < 0.001). LHX6 knockout increased erlotinib resistance and cell migration ability in HCC827 cells, and LHX6 overexpression inhibited erlotinib resistance and cell migration ability in HCC827/ER cells. In addition, LHX6 mediated erlotinib resistance and cell migration ability in HCC827/ER cells via the Wnt/β-catenin pathway. Immunohistochemical staining showed lower LHX6 expression in lung cancer specimens relative to peri-cancer specimens, and there were no associations of LHX6 expression with pathologic stage, gender, age or tumor size in lung cancer patients (P > 0.05).Conclusion: LHX6 down-regulation may induce EGFR-TKIs resistance and increase the migration ability of HCC827/ER cells via activation of the Wnt/β-catenin pathway.Keywords: non-small-cell lung cancer, epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI, LIM homeobox domain 6, LHX6, erlotinib, chemotherapy resistance, Wnt/β-catenin signaling

Yanling Lin,1,* Lingzhi Wang,2,* Wenxiao Luo,1,* Xiaohan Zhou,1 Yuting Chen,1 Kaifan Yang,3 Jinrong Liao,4 Dehua Wu,1 Longmei Cai1 1Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2First Clinical Medical College, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Second Clinical Medical College, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dehua Wu; Longmei CaiDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of ChinaTel +86 186 0206 2748; +86 134 5020 5073Email wudehua.gd@gmail.com; cailongmeibestlove@163.comPurpose: Nasopharyngeal carcinoma (NPC) is among the most common malignancies derived from the epithelium of the nasopharynx. To date, the regulatory networks involved in NPC have not been fully identified. Previous studies revealed multiple loss-of-function mutations in NPC and specifically in cylindromatosis lysine 63 deubiquitinase (CYLD); however, the exact role of CYLD in NPC progression and its potential mechanism remains unclear.Methods: We performed immunohistochemical (IHC) staining and real-time quantitative polymerase chain reaction (qPCR) to measure CYLD expression in NPC tissues, and Western blot was conducted to determine CYLD levels in NPC cell lines. Cell proliferation was detected by CCK8 assay and colony formation analysis, and apoptosis was determined by Annexin V/propidium iodide staining. Potential targets of CYLD were verified by co-immunoprecipitation and mass spectrometry. Xenograft assay was conducted to confirm the role of CYLD in vivo.Results: We found that CYLD levels were significantly decreased in both NPC tissues and cell lines, and that CYLD overexpression inhibited NPC cell proliferation and promoted apoptosis. Additionally, we revealed that CYLD bound and upregulated N-Myc downstream regulated 1 (NDRG1), and that silencing NDRG1 abolished the tumor-suppressor effect of CYLD on NPC cells. Furthermore, CYLD suppressed tumor growth in xenograft mice models.Conclusion: These results suggest CYLD as a tumor suppressor, potential biomarker for diagnosing NPC, and therapeutic target.Keywords: NPC, CYLD, proliferation, apoptosis, NDRG1

Yanxia Sun,*,1,2 Xiaolan Lai,*,3 Yue Yu,1,2 Jieyu Li,2,4 Lei Cao,3 Wansong Lin,2,4 Chuanzhong Huang,2,4 Jinrong Liao,2,4 Wei Chen,1,2 Chao Li,5 Chunkang Yang,6 Mingang Ying,6 Qiang Chen,3 Yunbin Ye2,41School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian Province, People’s Republic of China; 2Laboratory of Immuno-Oncology, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China; 3Department of Medical Oncology, Union Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People’s Republic of China; 4Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, Fujian Province, People’s Republic of China; 5Department of Pathology, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China; 6Department of Abdominal Surgery, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China*These authors contributed equally to this workBackground: Inhibitor of DNA binding 1 (Id1) is upregulated in multiple cancers, and Id1overexpression correlates with cancer aggressiveness and poor clinical outcomes in cancer patients. However, its roles in cancer stem-like cells (CSCs) and epithelial-mesenchymal transition (EMT) are still elusive.Purpose: This study aimed to examine the role of Id1 on the mediation of CRC stemness and explore the underlying mechanisms.Methods: Id1 and CD133 expression was detected by qPCR assay and immunohistochemistry (IHC) in normal mucosal and primary colorectal cancer (CRC) specimens. Id1 was stably knocked down (KD) in human CRC cell lines. Spheres forming assay and tumorigenic assay were performed to evaluate self-renewal capacity and tumor initiation. Expression of CSC- and EMT-related markers and TCF/LEF activity were assessed in HCT116 cells after Id1KD.Results: qPCR assay showed higher Id1 and CD133 expression in CRC specimens than in normal mucosal specimens (P