Lineage transition in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of non-small cell lung cancer, as implicated by clinical observation of mixed ADC and SCC pathologies in adenosquamous cell carcinoma, remains a fundamental yet unsolved question. Here we provide in vivo evidence showing the transdifferentiation of lung cancer from ADC to SCC in mice: Lkb1-deficient lung ADC progressively transdifferentiates into SCC, via a pathologically mixed mAd-SCC intermediate. We find that reduction of lysyl oxidase (Lox) in Lkb1-deficient lung ADC decreases collagen disposition and triggers extracellular matrix remodelling and upregulates p63 expression, a SCC lineage survival oncogene. Pharmacological Lox inhibition promotes the transdifferentiation, whereas ectopic Lox expression significantly inhibits this process. Notably, ADC and SCC show differential responses to Lox inhibition. Collectively, our findings demonstrate the de novo transdifferentiation of lung ADC to SCC in mice and provide mechanistic insight that may have important implications for lung cancer treatment.

The National Key Research and Development Program of China, the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, the Guangdong Province Natural Science Foundation, the Career Development Fellowship of Australian National Health and Medical Research Council, and the Early Career Fellowship of Australian National Health and Medical Research Council.

Background Exosomes as the main therapeutic vectors of mesenchymal stem cells (MSC) for inflammatory bowel disease (IBD) treatment and its mechanism remain unexplored. Tumor necrosis factor-α stimulated gene 6 (TSG-6) is a glycoprotein secreted by MSC with the capacities of tissue repair and immune regulation. This study aimed to explore whether TSG-6 is a potential molecular target of exosomes derived from MSCs (MSCs-Exo) exerting its therapeutic effect against colon inflammation and repairing mucosal tissue. Methods Two separate dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD mouse models were intraperitoneally administered MSCs-Exo extracted from human umbilical cord MSC (hUC-MSC) culture supernatant. Effects of MSCs-Exo on intestinal inflammation, colon barrier function, and proportion of T cells were investigated. We explored the effects of MSCs-Exo on the intestinal barrier and immune response with TSG-6 knockdown. Moreover, recombinant human TSG-6 (rhTSG-6) was administered exogenously and colon inflammation severity in mice was evaluated. Results Intraperitoneal injection of MSCs-Exo significantly ameliorated IBD symptoms and reduced mortality rate. The protective effect of MSCs-Exo on intestinal barrier was demonstrated evidenced by the loss of goblet cells and intestinal mucosa permeability, thereby improving the destruction of tight junctions (TJ) structures and microvilli, as well as increasing the expression of TJ proteins. Microarray analysis revealed that MSCs-Exo administration downregulated the level of pro-inflammatory cytokines and upregulated the anti-inflammatory cytokine in colon tissue. MSCs-Exo also modulated the response of Th2 and Th17 cells in the mesenteric lymph nodes (MLN). Reversely, knockdown of TSG-6 abrogated the therapeutic effect of MSCs-Exo on mucosal barrier maintenance and immune regulation, whereas rhTSG-6 administration showed similar efficacy to that of MSCs-Exo. Conclusions Our findings suggested that MSCs-Exo protected against IBD through restoring mucosal barrier repair and intestinal immune homeostasis via TSG-6 in mice.

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Long noncoding RNA LINC00261 has been experimentally validated to function as a tumor suppressor in several cancers, but its pathological role and functional mechanism in non–small cell lung cancer (NSCLC) are largely unclear. In this study, LINC00261 was delineated in NSCLC to be significantly downregulated in cancer tissues compared with corresponding adjacent normal tissues. Low expression of LINC00261 predicted worse survival for patients with NSCLC. Overexpression of LINC00261 in NSCLC cell lines inhibited cell proliferation and invasion, meanwhile promoted apoptosis. Subcellular fractionation assay showed that LINC00261 existed mainly in the cytoplasm of NSCLC A549 cells and luciferase assay validated its direct interaction with miR‐522‐3p. Overexpression of miR‐522‐3p significantly ameliorated suppressive effects of LINC00261 on proliferation and invasion of NSCLC cells. Besides, miR‐522‐3p was found to be able to directly combine with the 3′‐untranslated region of SFRP2, which was generally regarded as a suppressor of Wnt signaling. Further quantitative reverse transcription polymerase chain reaction and Western blot experiments showed that LINC00261 upregulation potentiated the expression of SFRP2 and inhibited Wnt signaling pathway, which could both be reversely modulated by miR‐522‐3p. Taken together, our study demonstrated that LINC00261 suppressed NSCLC cells progression via sponging miR‐522‐3p and inhibiting Wnt signaling. These results supported us to better understand the pathogenic mechanism of NSCLC and revealed a potential molecular target for this fatal disease.

BackgroundMelanosomes are specialized membrane-surrounded organelles, which are involved in the synthesis, storage and transport of melanin. Glycoprotein (transmembrane) non-metastatic melanoma protein b (GPNMB), a melanosome-specific structural protein, shares significant amino acid sequence homology with Pmel-17. Proteomic analysis demonstrated that GPNMB is present in all stages (I-IV) of melanosomes. However, little is known about the role of GPNMB in melanosomes.Methodology/Principal FindingsUsing real-time quantitative PCR, Western blotting and immunofluorescence analysis, we demonstrated that the expression of GPNMB in PIG1 melanocytes was up-regulated by ultraviolet B (UVB) radiation. Transmission electron microscopy analysis showed that the total number of melanosomes in PIG1 melanocytes was sharply reduced by GPNMB-siRNA transfection. Simultaneously, the expression levels of tyrosinase (Tyr), tyrosinase related protein 1 (Trp1), Pmel17/gp100 and ocular albinism type 1 protein (OA1) were all significantly attenuated. But the expression of microphthalmia-associated transcription factor (MITF) was up-regulated. Intriguingly, in GPNMB silenced PIG1 melanocytes, UVB radiation sharply reduced MITF expression.ConclusionOur present work revealed that the GPNMB was critical for the formation of melanosomes. And GPNMB expression down-regulation attenuated melanosome formation in a MITF-independent fashion.

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