Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells.

Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non-small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDH+CD44+CD24- pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC.Significance: This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities. Cancer Res; 78(8); 1986-99. ©2018 AACR.

The effect of cyclooxygenase-2 (COX-2) inhibition on human prostate cancer induced osteoblastic and osteolytic lesions in bone.

BACKGROUND: The mechanism of bone formation by osteoblastic prostate cancer metastases is not well defined. Using knockout mice, it has been demonstrated that prostaglandins produced by COX-2 are critical for fracture repair. Therefore, our aim was to determine if COX-2 plays a role in the bone formation in osteoblastic prostate cancer metastases in bone. MATERIALS AND METHODS: We assessed the influence of pharmacologic COX-2 inhibition in a SCID mouse intratibial injection model of bone metastasis using two human prostate cancer cell lines that produce either osteoblastic lesions (LAPC-9) or osteolytic lesions (PC-3, negative control). SC-58236, a COX-2 specific inhibitor, was used at a dose of 3 mg/Kg intraperitoneally 3 times per week in the Treatment groups for 8 weeks until sacrifice. RESULTS: Western blot for COX-2 demonstrated that LAPC-9 cells expressed high levels of COX-2 while PC-3 cells did not. Treatment with SC-58236 significantly reduced the size of osteoblastic lesions after LAPC-9 injection based on both radiographic and histomorphometric criteria compared to the control group. In contrast, large osteolytic lesions were seen in both control and SC-58236 treated animals after PC-3 cell injections. The results of this study indicate that COX-2 inhibition can decrease the size of osteoblastic lesions produced by LAPC-9, a human prostate cancer cell line that expresses high levels of COX-2. This treatment had no effect on the osteolytic activity of PC-3 cells. CONCLUSION: These findings suggest that the progression of osteoblastic metastases induced by human prostate cancer cells may be limited by COX-2 inhibitors.

IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis.

Based on studies by our group and others, we hypothesized that IL-7 may possess antifibrotic activities in an IFN-gamma-dependent and independent manner. Here, we have evaluated the antifibrotic therapeutic potential of IL-7 in both in vitro and in vivo pulmonary fibrosis models. IL-7 inhibited both TGF-beta production and signaling in fibroblasts and required an intact JAK1/STAT1 signal transduction pathway. IL-7-mediated inhibition of TGF-beta signaling was found to be associated with an increase in Smad7, a major inhibitory regulator in the SMAD family. In the presence of IL-7, Smad7 dominant negative fibroblasts restored TGF-beta-induced collagen synthesis, indicating that an IL-7-mediated increase in Smad7 suppressed TGF-beta signaling. Consistent with these in vitro findings, recombinant IL-7 decreased bleomycin-induced pulmonary fibrosis in vivo, independent of IFN-gamma. The antifibrotic activities of IL-7 merit further basic and clinical investigation for the treatment of pulmonary fibrosis.