miR­20b promotes growth of non­small cell lung cancer through a positive feedback loop of the Wnt/ß­catenin signaling pathway.

microRNAs (miRNAs or miRs) are endogenous noncoding single­stranded RNA molecules that can regulate gene expression by targeting the 3'­untranslated region and play an important role in many biological and pathological processes, such as inflammation and cancer. In this study, we found that miR­20b was significantly increased in human non­small cell lung cancer (NSCLC) cell lines and patient tissues, suggesting that it may possess a carcinogenic role in lung cancer. This miRNA promoted the proliferation, migration and invasion of NSCLC cells by targeting and downregulating the expression of adenomatous polyposis coli (APC), which is a negative regulator of the canonical Wnt signaling pathway. Wnt signaling activation may increase transcription of miR­20b. Therefore, miR­20b and canonical Wnt signaling were coupled through a feed­forward positive feedback loop, forming a biological regulatory circuit. Finally, an in vivo investigation further demonstrated that an increase in miR­20b promoted the growth of cancer cells. Overall, our findings offer evidence that miR­20b may contribute to the development of NSCLC by inhibiting APC via the canonical Wnt signaling pathway.

Honokiol Inhibits Proliferation, Invasion and Induces Apoptosis Through Targeting Lyn Kinase in Human Lung Adenocarcinoma Cells.

Honokiol is a natural compound with small molecular structure and extracted from bark of magnolia trees. The biological activities of honokiol include anti-oxidation, anti-inflammation as well as anti-tumor. However, their mechanism remains unknown. In this study, A549 cell line and EGFR-mutant cell line PC-9 with higher expression level of Lyn than A549 cells were used to assess the anti-tumor effects of honokiol. As shown in this study, honokiol is an effective drug on inhibiting proliferation and inducing apoptosis depended on Lyn and EGFR signal pathway regulated by Lyn, and its efficacy is stronger in PC-9 cells than A549 cells. In addition, this anti-tumor effect in PC-9 cells was weakened by Lyn-knockdown. Taken together, this study indicated the mechanism of honokiol on lung adenocarcinoma and provides a possibility of honokiol as an effective anti-tumor medicine.

Suppression of Lipogenesis via Reactive Oxygen Species-AMPK Signaling for Treating Malignant and Proliferative Diseases.

AIMS: Systemic diseases often have common characteristics. The aim of this study was to investigate the feasibility of targeting common pathological metabolism to inhibit the progression of malignant and proliferative diseases. RESULTS: Gefitinib-resistant (G-R) nonsmall-cell lung cancer (NSCLC) and rheumatoid arthritis (RA) were studied as conditions representative of malignant and proliferative diseases, respectively. Strong lipogenic activity and high expression of sterol regulatory element-binding protein 1 (SREBP1) were found in both G-R NSCLC cells and synovial fibroblasts from RA patients (RASFs). Berberine (BBR), an effective suppressor of SREBP1 and lipogenesis regulated through reactive oxygen species (ROS)/AMPK pathway, selectively inhibited the growth of G-R NSCLC cells and RASFs but not that of normal cells. It effectively caused mitochondrial dysfunction, activated ROS/AMPK pathway, and finally suppressed cellular lipogenesis and cell proliferation. Addition of ROS blocker, AMPK inhibitor, and palmitic acid significantly reduced the effect of BBR. In an in vivo study, treatment of BBR led to significant inhibition of mouse tumor xenograft growth and remarkably slowed down the development of adjuvant-induced arthritis in rats. Innovation and Conclusion: Targeting ROS/AMPK/lipogenesis signaling pathway selectively inhibited the growth of G-R NSCLC cells and the progress of RASFs in vitro and in vivo, which provides a new avenue for treating malignancies and proliferative diseases. Antioxid. Redox Signal. 28, 339-357.

Identification of a New Potent Inhibitor Targeting KRAS in Non-small Cell Lung Cancer Cells.

KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is an oncogenic driver with mutations in 30% of non-small cell lung cancer (NSCLC). However, there is no effective clinical drug even though it has been identified as an oncogene for 30 years. In this study, we identified a small molecule inhibitor compound 0375-0604 targeting KRAS by using molecular docking based virtual screening approach. Compound 0375-0604 had a good binding affinity to KRAS in vitro and exhibited cytotoxicity in oncogenic KRAS expressing NSCLC cell lines. Further mechanism study showed that compound 0375-0604 can block the formation of the complex of guanosine triphosphate (GTP) and KRAS in vitro. In addition, compound 0375-0604 inhibited KRAS downstream signaling pathway RAF/MEK/ERK and RAF/PI3K/AKT. Finally, we also found that this compound can inhibit the cell growth through G2/M cell cycle arrest and induce apoptosis on the NSCLC cell lines harboring KRAS mutation. Therefore, compound 0375-0604 may be considered as a potential KRAS inhibitor for treatment of NSCLC carrying KRAS oncogene.