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Abstract The Wnt pathway is frequently dysregulated in many cancers, underscoring it as a therapeutic target. Wnt inhibitors have uniformly failed in clinical trials. Here, we report a mechanism of WNT pathway activation through the Semaphorin 3 C neurodevelopmental program in glioma stem-like cells. Sema3C directs β-catenin nuclear accumulation in a Rac1-dependent process, leading to transactivation of Wnt target genes. Sema3C-driven Wnt signaling occurred despite suppression of Wnt ligand secretion, suggesting that Sema3C drives canonical Wnt signaling independent of Wnt ligand binding. In a mouse model of glioblastoma, combined depletion of Sema3C and β-catenin partner TCF1 extended animal survival more than single target inhibition alone. In human glioblastoma, Sema3C expression and Wnt pathway activation were highly concordant. Since Sema3C is frequently overexpressed in glioblastoma, Sema3C signaling may be a significant mechanism of resistance to upstream Wnt pathway inhibitors. Dual targeting of Sema3C and Wnt pathways may achieve clinically significant Wnt pathway inhibition.

Tracheobronchopathia osteoplastica (TO), is an underreported affliction characterized by squamous metaplasia and heterotopic bone formation in trachea and bronchi. Here the authors apply functional, as well as genome-wide transcriptional and epigenetic profiling to identify airway basal cells dysfunction underlying TO.

Abstract Colorectal carcinoma (CRC) has a high morbidity and mortality. Current studies have confirmed a variety of microRNA polymorphisms were associated with tumor susceptibility, however, the mechanisms are still unknown. In this study, we were aimed to clarify how polymorphism rs2682818 participated in the progression of CRC. First of all, the differential expression of miR-618 was assessed by quantitative real-time polymerase chain reaction in CRC patients with different genotypes of polymorphism rs2682818, including homozygous (TT) genotype, homozygous (GG) genotype and heterozygous (TG) genotype. Secondly, plasmids carried miR-168 precursor sequences harboring rs2682818 (SNP type) or without rs2682818 (wild type) were transfected into 293T cells to verify that polymorphism rs2682818 affected miR-618 expression. Thirdly, CCK-8 assay, flow cytometry assay, transwell assay and mouse xenograft assay were performed to measure the biological functions of miR-618 in CRC. Fourthly, the candidate target genes of miR-618 which were predicted by bioinformatics tools were verified by luciferase reporter assay. Finally, in order to explain the potential molecular mechanisms, western blotting was performed to demonstrate the differential expression and phosphorylation of pathway related proteins. The results showed that miR-618 was down-regulated in colon cancer, especially in CRC patients with rs2682818 GG homozygous genotype. Higher expression of mature miR-618 occurred in patients with TT homozygous genotype, and these patients usually had a longer survival time. Moreover, miR-618 mimic obviously impaired the growth and invasion ability of CRC cells, and miR-618 mimic also remarkably promoted CRC cell apoptosis. Our luciferase experiments confirmed that TIMP1 was a target of miR-618 in CRC cells. Knockdown of TIMP1 also significantly inhibited the malignant cytological features of CRC, including malignant growth and invasion as well as apoptosis resistance. In summary, polymorphism rs2682818 participated in the progression of CRC via affecting the expression of mature miR-618 in CRC cells, and miR-618 inhibited the progression of CRC via targeting TIMP1expression.

Abstract Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

Abstract The knowledge of airway length is the theoretical basis in the diagnosis and management of airway disease. The objective of this study is to measure the length of trachea and left and right main bronchus in Chinese Shanghai population. A total of 153 consecutive adult patients with minor pulmonary disease in Xinhua hospital were enrolled for bronchoscopy examination. Measurements were conducted on head and neck neutral position and height, weight and age for each patient were recorded either. Student t test and multiple linear regression was used to compare means between males and females and to analyze correlation among height, weight, sexual dimorphism and the lengths of the trachea and bronchus. The lengths of the trachea and left main bronchus are significantly different between male and female patients (P

The tumour microenvironment plays an important role in promoting glioblastoma. Here, the authors show that glioma stem cells secrete WISP1, which promotes both the survival of the stem cells and tumour-associated macrophages.