With the development of new molecularly targeted therapies and immunotherapies, the landscape of treatment and outcome for lung cancer has been greatly improved. However, the 5-year overall survival rate of lung cancer remains poor and no more than 20%. As a result, it is essential to develop effective screening biomarkers and potential therapy targets to improve the prognosis of lung cancer patients. As a new class of endogenous functional noncoding RNAs, CircRNAs have been reported to exert important regulatory roles in tumor pathogenesis and progression. The expression and function of circRNAs in lung adenocarcinoma remain not fully understood. In this study, we systematically determined the expression and potential of hsa_circ_0009618 in lung adenocarcinoma. To our knowledge, this is the first study on hsa_circ_0009618 in lung adenocarcinoma.
Due to their covalently closed conformation and high stability than conventional linear RNA, circRNAs can not be easily degraded by RNA exonuclease (13, 14). These characteristics of circRNAs have successfully attracted the attention of researchers. Increasing findings have suggested that circRNAs are abnormally expressed in many human tumors, and the abnormal circRNA expression is significantly correlated with the initiation and progression of tumors, including gastric cancer, breast cancer, and colorectal cancer (15–17). In our study, we determined the expression profiles of circRNAs in lung adenocarcinoma using microarrays. Our results were consistent with previous studies and suggested that circRNAs are also abnormal expressed in lung adenocarcinoma, further suggesting circRNAs could play an important role in the development of lung adenocarcinoma. After confirm of the upregulation of hsa_circ_0009618 in both lung adenocarcinoma cell lines and lung adenocarcinoma tissues. These observations lead us to explore the role of hsa_circ_0009618 in tumor proliferation and migration.
Many studies about the possible role of circRNAs have emerged in recent years. Previous findings suggested that dysregulation of circRNAs have been involved in the progression of various tumors. In gastric cancer, Shan et al. reviewed recent studies and found that many circRNAs are dysregulated in GC tissues, and can regulate cell proliferation, apoptosis, invasion, metastasis, and drug resistance (18). Moreover, circRNAs can act as potential diagnostic and prognosis markers for gastric cancer. In hepatocellular carcinoma, A paper from Su et al. indicated that upregulation of circRNA Cdr1as is involved in the progression of hepatocellular carcinoma via accelerate hepatocellular carcinoma cells to proliferate and migration (19). As for lung cancer, there are also many findings on the oncogenic role of circRNAs in tumor cell proliferation and migration (20, 21). However, the function of hsa_circ_0009618 has not been investigated in lung adenocarcinoma. In the present study, we found that hsa_circ_0009618 plays an oncogenic role in lung adenocarcinoma by inhibiting lung adenocarcinoma cell proliferation and invasion, and inducing apoptosis. Thus, hsa_circ_0009618 could be the cause of tumor progression in hsa_circ_0009618. Our findings on the oncogenic role of hsa_circ_0009618 agree with those reports by previous studies on circRNAs. In this study, we showed for the first time the oncogenic role of hsa_circ_0009618 in lung adenocarcinoma.
The oncogenic role of hsa_circ_0009618 in lung adenocarcinoma promote us the explore the detailed underlying mechanisms. It is well known that some circRNAs can act as microRNA sponges and then regulate the pathway activity by targeting miRNAs (22, 23). Cao et al. demonstrated that circRNF20 can act as a miRNA sponge to harbor miR-487a and reduce the expression of its target gene HIF-1a, exerting important role in the energy metabolism of tumor development (24). A paper from Yang et al. reported that hsa_circRNA_0088036 can sponge miR-140-3p and promote bladder cancer progression via ceRNA and miR-140-3p/FOXQ1 signaling (25). In the present study, we identified a significantly upregulated hsa_circ_0009618 in lung adenocarcinoma tissues and hsa_circ_0009618 binds to miR-153-3p. Previous studies have reported that the expression of miR-153-3p is involved in the development of many tumors. Jia et al. investigated that miR-153-3p can regulate SphK2 to suppress the growth and metastasis in gastric cancer (26). Moreover, Deng et al. reported that miR-153-3p is low expressed in thyroid tumors and cells, miR-153-3p inhibit E3F3 to suppress tumor growth and increase apoptosis in thyroid tumor (27). In our study, we found that hsa_circ_0009618/miR-153-3p as a ceRNA and targets Hmga2 to promote the progression of lung adenocarcinoma, thus forming hsa_circ_0009618-miR-153-3p-Hmga2 axis. Therefore, our study indicates that hsa_circ_0009618 may act as an oncogene to promote lung adenocarcinoma progression and used as a potential therapy target and prognostic marker.
In conclusion, our finding suggested that hsa_circ_0009618 is increased in lung adenocarcinoma. Functionally, knockdown hsa_circ_0009618 negatively regulates the growth, invasion, and migration of lung adenocarcinoma cells, and inhibits tumor growth in vivo. In addiction, miR-153-3p/Hmga2 is demonstrated as the targets of hsa_circ_0009618 in regulation the development of lung adenocarcinoma. Our study suggests that hsa_circ_0009618 is a potential biomarker for the therapy of lung adenocarcinoma.