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Objective: Synchronous multiple ground-glass nodules (SM-GGNs) are a distinct entity of lung cancer which has been emerging increasingly in recent years in China. The oncogenesis molecular mechanisms of SM-GGNs remain elusive. Methods: We investigated single nucleotide variations (SNV), insertions and deletions (INDEL), somatic copy number variations (CNV), and germline mutations of 69 SM-GGN samples collected from 31 patients, using target sequencing (TRS) and whole exome sequencing (WES). Results: In the entire cohort, many known driver mutations were found, including EGFR (21.7%), BRAF (14.5%), and KRAS (6%). However, only one out of the 31 patients had the same somatic missense or truncated events within SM-GGNs, indicating the independent origins for almost all of these SM-GGNs. Many germline mutations with a low frequency in the Chinese population, and genes harboring both germline and somatic variations, were discovered in these pre-stage GGNs. These GGNs also bore large segments of copy number gains and/or losses. The CNV segment number tended to be positively correlated with the germline mutations (r = 0.57). The CNV sizes were correlated with the somatic mutations (r = 0.55). A moderate correlation (r = 0.54) was also shown between the somatic and germline mutations. Conclusion: Our data suggests that the precancerous unstable CNVs with potentially predisposing genetic backgrounds may foster the onset of driver mutations and the development of independent SM-GGNs during the local stimulation of mutagens.

MicroRNA-200 (miR-200) has emerged as a regulator of the PI3K/AKT pathway and cancer cell growth. It was reported that miR-200 can activate PI3K/AKT by targeting FOG2 (friend of GATA 2), which directly binds to the p85α regulatory subunit of PI3K. We found that miR-200 was elevated in early stage lung adenocarcinomas when compared with normal lung tissues, and the expression of miR-200 promoted the tumor spheroid growth of lung adenocarcinoma cells. We show that AKT activation was essential for such oncogenic action of miR-200. However, depletion of FOG2 had little effect on AKT activation. By performing a reverse-phase protein array, we found that miR-200 not only activated AKT but also concomitantly inactivated S6K and increased IRS-1, an S6K substrate that is increased on S6K inactivation. Depletion of IRS-1 partially inhibited the miR-200-dependent AKT activation. Taken together, our results suggest that miR-200 may activate AKT in lung adenocarcinoma cells through a FOG2-independent mechanism involving IRS-1. Our findings also provide evidence that increased miR-200 expression may contribute to early lung tumorigenesis and that AKT inhibitors may be useful for the treatment of miR-200-dependent tumor cell growth. © 2015 IUBMB Life, 67(9):720-725, 2015 [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common types of cancer, with the highest mortality rate worldwide. MicroRNAs play notable roles in the chemotherapeutic effects of anticancer drugs. The present study used reverse transcription-quantitative PCR, western blotting and cell migration and invasion assays to reveal the role of let-7f-1-3p in non-small cell lung cancer (NSCLC) and explore the effect of let-7f-1-3p on doxorubicin (DOX) treatment. It was demonstrated that the levels of let-7f-1-3p in carcinoma tissues were lower compared with those in paracarcinoma tissues. Thus, let-7f-1-3p may act as a suppressor gene. The present study also explored the role of let-7f-1-3p in A549 and NCI-H1975 cells. Results revealed that let-7f-1-3p could inhibit the viability, migration and invasion of NSCLC cells and induce their apoptosis. Integrin β1 acted as a target gene regulated by let-7f-1-3p. This suggested that let-7f-1-3p could enhance DOX-inhibited cell viability, migration and invasion in vitro. Overall, the present study demonstrated that let-7f-1-3p may act as a target for drug design and lung cancer therapy. [ABSTRACT FROM AUTHOR]

Lung adenocarcinomas from never smokers account for approximately 15 to 20% of all lung cancers and these tumors often carry genetic alterations that are responsive to targeted therapy. Here we examined mutation status in 10 oncogenes among 89 lung adenocarcinomas from never smokers. We also screened for oncogene fusion transcripts in 20 of the 89 tumors by RNA-Seq. In total, 62 tumors had mutations in at least one of the 10 oncogenes, including EGFR (49 cases, 55%), K-ras (5 cases, 6%), BRAF (4 cases, 5%), PIK3CA (3 cases, 3%), and ERBB2 (4 cases, 5%). In addition to ALK fusions identified by IHC/FISH in four cases, two previously known fusions involving EZR- ROS1 and KIF5B-RET were identified by RNA-Seq as well as a third novel fusion transcript that was formed between exons 1-9 of SND1 and exons 2 to 3′ end of BRAF. This in-frame fusion was observed in 3/89 tested tumors and 2/64 additional never smoker lung adenocarcinoma samples. Ectopic expression of SND1-BRAF in H1299 cells increased phosphorylation levels of MEK/ERK, cell proliferation, and spheroid formation compared to parental mock-transfected control. Jointly, our results suggest a potential role of the novel BRAF fusion in lung cancer development and therapy. [ABSTRACT FROM AUTHOR]

Abstract The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or –selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-β1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-β1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking. [ABSTRACT FROM AUTHOR]

Muscle wasting is a decline in skeletal muscle mass and function that is associated with aging, obesity, and a spectrum of pathologies including cancer. Cancer-associated wasting not only reduces quality of life, but also directly impacts cancer mortality, chemotherapeutic efficacy, and surgical outcomes. There is an incomplete understanding of the role of tumor-derived factors in muscle wasting and sparse knowledge of how these factors impact in vivo muscle regeneration. Here, we identify several cytokines/chemokines that negatively impact in vitro myogenic differentiation. We show that one of these cytokines, CXCL1, potently antagonizes in vivo muscle regeneration and interferes with in vivo muscle satellite cell homeostasis. Strikingly, CXCL1 triggers a robust and specific neutrophil/M2 macrophage response that likely underlies or exacerbates muscle repair/regeneration defects. Taken together, these data highlight the pleiotropic nature of a novel tumor-derived cytokine and underscore the importance of cytokines in muscle progenitor cell regulation. [ABSTRACT FROM AUTHOR]