The apelin receptor (APLNR) is a GPCR involved in many pathophysiological processes; however, the correlation between APLNR expression and nasopharyngeal carcinoma (NPC) has not been reported. In this study, we used cDNA microarray data to determine APLNR expression levels in NPC tissues. We found that APLNR expression was reduced in NPC tissues compared with noncancerous nasopharyngeal epithelial tissues. Subsequently, a large‐scale sample of 1015 tissues was used to validate this discovery and explore the relationship between APLNR expression and prognosis of NPC. Expression levels of APLNR in NPC tissues were indeed down‐regulated. Furthermore, positive expression of APLNR in NPC predicted a better prognosis (disease‐free survival: P = 0.001; overall survival: P < 0.001). Moreover, ingenuity pathway analysis revealed that an indirect interaction existed between APLNR and retinoic acid (RA) in the cancer regulatory network. Consistently, after treatment with all‐trans‐RA (ATRA), we found that APLNR was significantly up‐regulated in NPC cell lines (5‐8F and HNE1), and proliferation of NPC cells was inhibited. Cell cycle arrest occurred in the G0/G1 phase. In contrast, knockdown of APLNR diminished ATRA‐induced growth inhibition of NPC cells. In addition, we surprisingly found that APLNR also played an important role in migration and invasion of NPC. Wound‐healing and Transwell assays revealed that APLNR overexpression led to reduced migratory and invasive properties in 2 NPC cell lines. Western blot results revealed that hallmarks of epithelial‐mesenchymal transition (EMT) were altered as well, suggesting that APLNR was capable of inhibiting EMT in NPC cells. Our study further demonstrated that low expression of APLNR promoted EMT in NPC cells by activating the PI3K‐protein kinase B‐mammalian target of rapamycin signaling pathway. Taken together, our data suggest that APLNR could potentially predict prognosis for patients with NPC and inhibit proliferation, migration, invasion, and EMT in nasopharyngeal cancer cells.—Liu, Y., Liu, Q., Chen, S., Liu, Y., Huang Y., Chen, P., Li, X., Gao, G., Xu, K., Fan, S., Zeng Z., Xiong W., Tan, M., Li, G., Zhang W. APLNR is involved in ATRA‐induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K‐Akt‐mTOR signaling. FASEB J. 33, 11959‐11972 (2019). http://www.fasebj.org

Background Cyclin D1 is an essential part of oncogenic transformation. We previously proved that cyclin D1 was upregulated in nasopharyngeal carcinoma (NPC) and promoted the NPC cell proliferation. But the association between cyclin D1 and the clinical outcome of NPC has not yet been determined. The study explores the possible relevance between the cyclin D1 expression and clinical parameters and its predictive value of prognosis in NPC patients. Methods We analyzed the clinical data from 379 NPC patients and 112 non‐NPC patients in our previous study, which made further statistics. Receiver operating curve (ROC) was applied to select the optimal cutoff points. By analyzing the clinical data from 101 NPC patients using Chi‐squared test, we estimated the relationship between the cyclin D1 expression level and clinicopathological parameters. We also used Kaplan‐Meier method and log‐rank test assess and compared the disease‐free survival (DFS) rate and overall survival (OS) rate. The Cox proportional hazards model was adopted to perform the univariate and multivariate analyses. Result Receiver operating curve analysis reported that cyclin D1 was used to differentiate between NPC patients and non‐NPC patients ( P < .001, sensitivity: 53.6%, specificity: 85.7%, AUC = 0.752). Cyclin D1 was positively correlated with lymph node metastasis ( P = .015). A survival analysis of the 101 NPC patients indicated that the positive expression of cyclin D1 was predictive of a good prognosis (DFS: P = .010, OS: P = .019). Multivariate analysis showed that cyclin D1 could be used independently to predict NPC patients' prognosis (DFS: P = .038). Conclusion The overexpression of cyclin D1 is a good prognostic marker for NPC.

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