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: DSB repair is frequently associated with gene conversion. Results: Gene conversions at the site of a DSB and its surrounding regions are regulated differently. Conclusion: hMSH2, hMLH1, and hMRE11 play different roles in proximal and distal gene conversions. Significance: Delineating the mechanisms underlying DSB-induced gene conversion will help to decipher how mutations in DSB repair genes affect genome stability.
Increasing evidence indicates that the mismatch repair protein hMLH1 and DNA double-strand break (DSB) repair protein hMRE11 play multifunctional roles in various processes of DNA repair and damage response in human cells. Our previous studies have revealed a physical interaction between these two proteins and have suggested a role for hMRE11 in heteroduplex DNA repair and hMLH1-dependent DNA damage-induced G2 arrest. Here, we analyzed the effects of hMLH1-hMRE11 on homologous recombinational repair of an induced DSB and consequential heteroduplex repair at a single chromosomal locus by a newly developed reporter system. The results of these studies indicate that hMLH1 and hMRE11 display a synergistic anti-recombination effect and the hMLH1-mediated anti-recombination is at least partially dependent on its interaction with hMRE11, whereas the repair of heteroduplex DNA requires functional hMLH1 and hMRE11. Consistent with these results, chromatin immunoprecipitation (ChIP) analysis of the reporter locus demonstrates that DSB triggers the loading of hMLH1 and hMRE11 proteins to both the proximal region and the site containing heteroduplex DNA. However, in contrast to the proximal regions, loading of hMLH1-hMRE11 at the site of heteroduplex DNA also requires hMSH2, suggesting the involvement of DNA mismatch repair. In summary, our studies have provided evidence to suggest that, in addition to DNA damage response, hMLH1-hMRE11 are involved in at least two other DNA damage repair processes: anti-recombination and heteroduplex DNA repair. Our results implicate that mutations impairing the hMLH1-hMRE11 interaction might promote spontaneous chromosomal recombination between ectopic repetitive sequences and thereby increasing gene conversion and genomic instability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3927.
Background: Chromosome translocation is one of the most common chromosomal causes to T-cell acute lymphoblastic leukemia (T-ALL). Ku70 is one of the key factors of error-prone DNA repair that may end in translocation. So far, the direct correlation between Ku70 and translocation has not been assessed. Our study aimed to investigate the association of Ku70 and translocation in human lymphocytes after radiation and T-ALL. Methods: Peripheral blood lymphocytes (PBLs) from volunteers and human lymphocyte cell line AHH-1were irradiated with X-rays to form chromosome translocations. The frequency of translocation was detected by fluorescence in situ hybridization (FISH), meanwhile, the expression of Ku70 was also detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Furthermore, Ku70 interference, overexpression and chemical inhibition were used in AHH-1 cell lines to confirm the correlation. Finally, we detected the expression of Ku70 in T-ALL samples with or without translocation. Results: Expression of Ku70 and frequencies of translocation were both significantly increased in PBLs after irradiated by X-rays, and a positive correlation between the expression (both mRNA and protein level) of Ku70 and the frequency of translocation was detected (r = 0.4877, P = 0.004; r = 0.3038, P = 0.0358 respectively). Moreover, Ku70 interference decreased the frequency of translocations while the frequency of translocations was not significantly affected after Ku70 overexpression. The expression of Ku70 and frequencies of translocation were both significantly increased in cells after irradiated combined with chemical inhibition (P <0.01). The protein level and mRNA level of Ku70 in T-ALL with translocation were significantly higher than T-ALL with normal karyotype (P = 0.009, P = 0.049 respectively). Conclusions: Ku70 is closely associated with the frequency of chromosome translocation in human lymphocytes after radiation and T-ALL. Ku70 might be a radiation damage biomarker and a potential tumor therapy target.
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