Comprehensive genomic analyses of small cell lung cancer (SCLC) have revealed frequent mutually exclusive genomic amplification of MYC family members. Hence, it has been long suggested that they are functionally equivalent; however, more recently, their expression has been associated with specific neuroendocrine markers and distinct histopathology. Here, we explored a previously undescribed role of L-Myc and c-Myc as lineage-determining factors contributing to SCLC molecular subtypes and histology. Integrated transcriptomic and epigenomic analyses showed that L-Myc and c-Myc impart neuronal and non-neuroendocrine–associated transcriptional programs, respectively, both associated with distinct SCLC lineage. Genetic replacement of c-Myc with L-Myc in c-Myc–SCLC induced a neuronal state but was insufficient to induce ASCL1-SCLC. In contrast, c-Myc induced transition from ASCL1-SCLC to NEUROD1–SCLC characterized by distinct large-cell neuroendocrine carcinoma–like histopathology. Collectively, we characterize a role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular and histological subtypes.

BackgroundmiR-126 is a key regulator of oncogenic processes. It is functionally linked to cellular proliferation, survival and migration. Vascular endothelial growth factor A (VEGF-A), which is regarded as a tumorgenesis activator, could directly target miR-126 in several tumors. However, the mechanism in esophageal cancer remains unclear.Methods and resultsIn this study, the expression of miR-126 and VEGF-A were assessed in esophageal cancer tissues and esophageal cancer cell lines. We found that miR-126 has significantly lower expression in esophageal cancer tissues and esophageal cancer cell lines than in healthy tissues, while the expression of VEGF-A is high. Luciferase reporter assays were performed to investigate the relationship between VEGF-A and miR-126. We confirmed that VEGF-A is a target for miR-126. Furthermore, the proliferation of esophageal cancer cells with miR-126 overexpression and miR-126 knockdown was monitored using the MTT assay. The results showed that miR-126 could inhibit esophageal cancer cell proliferation in vitro. The effect of miR-126 was also detected in BALB/c nude mice with transplanted esophageal cancer cells. In vivo study showed that tumor growth was significantly suppressed by miR-126 overexpression.ConclusionsWe believe that restoring miR-126 levels may be a promising therapeutic approach in cases of esophageal cancer.

Sphingosine kinase1 (SphK1) is an oncogenic enzyme that regulates tumor cell apoptosis, proliferation and survival. SphK1 has been reported to promote the development of non-small cell lung cancer (NScLc), although the underlying mechanism remains to be determined. The aim of the present study was to examine the expression and function of SphK1 in NScLc and to explore the underlying molecular mechanism. The results of the present study demonstrated that SphK1 expression was upregulated in NScLc tissues and cell lines. Overexpression of SphK1 increased the proliferation and migration of NScLc cells. Additionally, overexpression of SphK1 induced expression of antiapoptotic and migration-associated genes, such as Bcl-2, matrix metallopeptidase 2 and cyclin d1. Of note, signal transducer and activator of transcription 3 (STAT3) was also activated in the SphK1-overexpressing cells. By treatment with a STAT3 inhibitor, it was demonstrated that the SphK1-induced changes in expression of target genes, as well as the increase in proliferation and migration of NScLc cells were mediated by STAT3. In conclusion, the effects of SphK1 overexpression on the development of NScLc were demonstrated to be mediated by the activation of STAT3. These results suggested that inhibition of the SphK1-STAT3 axis may be a potential strategy for the treatment of NScLc.

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