LUAD is a major lung cancer that is in a locally advanced or metastatic stage at the time of diagnosis, which leaves no time for early detection or treatment . The accurate diagnosis and prognosis may warrant timely treatment to potentially decrease the mortality. Therefore, it is essential to explore the molecular mechanisms of LUAD progression and identify the effective biomarkers contributing to better treatment and better overall prognosis for LUAD patients.
Growing experimental evidences have shown that circRNAs play important roles in many complicated human diseases, including malignant tumors [28–30]. Lately, lots of studies indicated that circRNAs could function as a tumor regulator in lung cancer [31–33]. As a type of high efficiency ceRNA, it could inhibit the binding of miRNAs to target genes and regulate the expression level of target genes by exerting a miRNA sequestering effect . However, the expression pattern and biological function of circRNAs in LUAD remain largely elusive. In present study, we constructed a circRNA-miRNA-mRNA ceRNA network to explore the regulatory mechanism of circRNAs involved in tumor progression. An integrated circRNA-associated ceRNA network, including 11 circRNAs, 8 miRNAs and 49 mRNAs, was established. The 11 cicRNAs identified in the ceRNA network were hsa_circ_0002191, hsa_circ_0002727, hsa_circ_0049271, hsa_circ_0050395, hsa_circ_0001974, hsa_circ_0004006, hsa_circ_0000641, hsa_circ_0079929, hsa_circ_0007788, hsa_circ_0001936, hsa_circ_0015278. We found that two of eleven circRNAs had been reported to be related to disease progression and pathogenesis. Peng et al. reported that hsa_circ_0015278 was significantly down-regulated in papillary thyroid carcinoma, showing interactive potential with two cancer-related miRNAs . Furthermore, several promising cancer-related genes that may be targets of the dysregulated hsa_circRNA_0015278/miR-141-3p/miR-200a-3p axis were identified to explore the pathogenesis of papillary thyroid carcinoma. Another circRNA, named hsa_circ_0079929, has been reported by Zou et al . They found that elevated expression of hsa_circRNA_0079929 might inhibit the expression of hsa-miR-26a-3p to increase aortic smooth muscle cells phenotype or apoptosis in thoracic aortic dissection. Although other circRNAs have not been reported previously, we could detect the interactive potential with miRNAs and target genes based on the constructed ceRNA network. For example, in circRNA-associated ceRNA network constructed in present study, hsa_circ_0001936 interacted with has-miR-142-5p and further might regulate its target genes, such as CAV2, FGD5 and S1PR1, which were involved in positive regulation of GTPase activity process. Such results indicated that hsa_circ_0001936 might play key roles in LUAD progression by regulating GTPase activity. Thus, the regulatory mechanism of these circRNAs speculated in ceRNA network requires further experimental investigation in future studies.
Limited by small sample size or lack of corresponding clinical data, it is not feasible to construct diagnostic or prognostic signatures for clinical application based on circRNAs at the current stage. However, extensive transcriptome data with corresponding clinical data provide us the possibility to construct clinically available diagnostic or prognostic signatures. In present study, we identified the key mRNA participating in the circRNA-associated ceRNA network based on STRING database and further constructed a three-gene prognostic signature for LUAD patients. The three-gene prognostic signature is composed of centrosomal protein 55 (CEP55), kinesin family member 14 (KIF14) and proline rich 11 (PRR11). CEP55 localizes to the centrosome of interphase cells and to the midbody during cytokinesis . Many studies have demonstrated that CEP55 was highly expressed in a variety of cancers and could be used as a diagnostic and prognostic marker for several cancers [38–40]. For LUAD, Fu et al. had reported that CEP55 was significantly up-regulated in LUAD patients and could be an independent prognostic factor . As a mitotic kinesin, KIF14 has been reported to serve oncogenic roles through the regulation of the cell cycle, DNA replication and DNA repair biological processes in a variety of malignancies, such as colorectal cancer , ovarian cancer , gastric cancer , prostate cancer , and so on. Zhang et al. had confirmed that KIF14 was notably up-regulated in tumor tissues of LUAD and the expression levels of the KIF14 exhibited a strongly correlation with OS . PRR11, located on chromosome 17q22, has been reported to be closely associated with cell cycle progression and was also demonstrated to participate in various biological processes in tumor cells, including cell invasion, migration and proliferation, by acting as an oncogene [47–50]. Ji et al. found that PRR11 was periodically expressed in a cell cycle-dependent manner. RNAi-mediated silencing of PRR11 caused S phase arrest and suppressed cellular proliferation, colony formation ability in lung cancer cells, demonstrating that PRR11 had a critical role in both cell cycle progression and tumorigenesis . All three genes are associated with tumor progression and prognosis, indicating that the three-gene signature could be served as clinically available prognostic signature to provide potential novel targets and promote individualized treatment. In addition, we found that all three genes were regulated by has-miR-144-3p interacting with hsa_circ_0002191 and hsa_circ_0002727, indicating that hsa_circ_0002191 and hsa_circ_0002727 might serve as potential regulators to affect gene expression and further influenced the progression and prognosis of LUAD patients. Thus, further experimental investigation needs to be implemented to explore the regulatory mechanism and prognostic ability of hsa_circ_0002191 and hsa_circ_0002727.