title: SPLUNC1 is associated with nasopharyngeal carcinoma prognosis and plays an important role in all-trans-retinoic acid-induced growth inhibition and differentiation in nasopharyngeal cancer cells.
abstract: Human SPLUNC1 can suppress nasopharyngeal carcinoma (NPC) tumor formation; however, the correlation between SPLUNC1expression and NPC patient prognosis has not been reported. In the present study, we used a large-scale sample of 1015 tissue cores to detect SPLUNC1 expression and its association with patient prognosis. SPLUNC1 expression was reduced in NPC samples compared to nontumor nasopharyngeal epithelium tissues. Positive expression of SPLUNC1 in NPC predicted a better prognosis (disease-free survival, P = 0.034; overall survival, P = 0.048). Cox's proportional hazards model revealed that SPLUNC1 could be a significant prognostic factor affecting disease-free survival (P = 0.027). A cDNA micro-array analyzed by significant analysis of micro-array (SAM) and ingenuity pathway analysis (IPA) revealed that an indirect interaction existed between SPLUNC1 and retinoic acid (RA) in the cancer regulatory network. To further investigate the molecular mechanisms involved, we utilized several bioinformatics tools and identified 12 retinoid X receptors heterodimer binding sites in the promoter region of the SPLUNC1 gene. The transcriptional activity of the SPLUNC1 promoter was up-regulated significantly by all-trans-retinoic acid (ATRA). SPLUNC1 and retinoic acid receptor expression were induced significantly by ATRA, and removal of ATRA led to a progressive loss of SPLUNC1 and retinoic acid receptor expression. ATRA inhibited proliferation and induced the differentiation of NPC cells. Interestingly, over-expression of SPLUNC1 sensitized NPC cells to ATRA, whereas knockdown of SPLUNC1 in HNE1 cells increased cell viability. Under SPLUNC1 knockdown conditions, differentiation was reversed by ATRA treatment. We concluded that SPLUNC1 could potentially predict prognosis for NPC patients and play an important role in ATRA-induced growth inhibition and differentiation in NPC cells.
authors.affiliation: Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Department of Medical Laboratory Science, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Carcinogenesis of Ministry of Health and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.
authors.forename: Wenling
authors.initials: W
authors.lastname: Zhang
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Zeng
authors.forename: Fang
authors.initials: F
authors.lastname: Wei
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.forename: David C
authors.initials: DC
authors.lastname: Schmitt
authors.forename: Songqing
authors.initials: S
authors.lastname: Fan
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Guo
authors.forename: Fang
authors.initials: F
authors.lastname: Liang
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Zixin
authors.initials: Z
authors.lastname: Liu
authors.forename: Zuping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Xiang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Donghai
authors.initials: D
authors.lastname: Huang
authors.forename: Ke
authors.initials: K
authors.lastname: Tang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Li
authors.forename: Xiayu
authors.initials: X
authors.lastname: Li
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D001665:Binding Sites; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; C485599:BPIFA1 protein, human; D006023:Glycoproteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014212:Tretinoin
keywords: SPLUNC1; all-trans-retinoic acid; differentiation; nasopharyngeal carcinoma; prognosis