The role of HGF-MET pathway and CCDC66 cirRNA expression in EGFR resistance and epithelial-to-mesenchymal transition of lung adenocarcinoma cells

Abstract

BackgroundEpithelial-to-mesenchymal transition (EMT) has, in recent years, emerged as an important tumor cell behavior associated with high metastatic potential and drug resistance. Interestingly, protein SUMOylation and hepatocyte growth factor could respectively reduce the effect of small molecule inhibitors on tyrosine kinase activity of mutated epidermal growth factor receptor of lung adenocarcinomas (LADC). The actual mechanism is yet to be resolved.MethodsImmunohistochemistry was used to stain proteins in LADC specimens. Protein expression was confirmed by Western blotting. In vitro, expression of proteins was determined by Western blotting and immunocytochemistry. Levels of circular RNA were determined by reverse transcription-polymerase chain reaction.ResultsSAE2 and cirRNA CCDC66 were highly expressed in LADC. Expression of SAE2 was mainly regulated by EGFR; however, expression of cirRNA CCDC66 was positively regulated by FAK and c-Met but negatively modulated by nAchR7α. EGFR-resistant H1975 also highly expressed cirRNA CCDC66. Immediate response of hypoxia increased phosphorylated c-Met, SAE2, and epithelial-to-mesenchymal transition. Either activation of FAK or silencing of nAchR7α increased cirRNA CCDC66.ConclusionsHGF/c-Met regulates expression of SAE2 and cirRNA CCDC66 to increase EMT and drug resistance of LADC cells. Multimodality drugs concurrently aiming at these targets would probably provide more benefits for cancer patients.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0557-9) contains supplementary material, which is available to authorized users.

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

“…circRNAs have emerged as novel players that are involved in various biological and pathological processes . Recent studies have demonstrated that many circRNAs are involved in tumorigenesis and progression . The relationship between circRNAs and cellular senescence in human malignancy, however, has never been reported before.…”

“…27 Recent studies have demonstrated that many circRNAs are involved in tumorigenesis and progression. 28,29 The relationship between circRNAs and cellular senescence in human malignancy, however, has never been reported before. We, for the first time, associated circLARP4 dysregulation with senescence in HCC.…”

Circ-CCDC66 Upregulates REXO1 Expression to Aggravate Cervical Cancer Progression Via Restraining miR-452-5p

“…In this study, we revealed that circ-CCDC66 acted as an oncogene in cervical cancer. Previous study has demonstrated that circ-CCDC66 mediates tumorigenesis via regulating multiple cellular functions, such as proliferation, migration, invasion and EMT levels [19,20,26]. Here, we found that knockdown of circ-CCDC66 attenuated cervical cancer cell proliferation, migration and invasion abilities in vitro, and inhibited cervical cancer cell growth in vivo.…”

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

“…CircCCDC66 is positively regulated by FAK (a marker of EMT) and HGF/c-Met, while it is negatively regulated by the acetylcholine receptor nAchR7α. However, reduction of circCCDC66 does not affect the resistance of H1975 cells to gefitinib or erlotinib but inhibits EMT and reduces cell sensitivity to cisplatin [118]. Hsa-circRNA-002178 enhances PD-L1 expression by sponging miR-34 to induce T cell exhaustion.…”

“…Upregulation of hsa_circ_0071799 affects miR-141, while downregulation of hsa_circ_ 0091931 affects miR-34c-5p, both of which may mediate osimertinib resistance [20]. CircCCDC66 and hsa-circRNA-002178 are highly expressed in lung adenocarcinoma (LUAD) cells [60,118]. CircCCDC66 is positively regulated by FAK (a marker of EMT) and HGF/c-Met, while it is negatively regulated by the acetylcholine receptor nAchR7α.…”