VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).

HOX transcript antisense RNA (HOTAIR), a long intergenic non-coding RNA (lncRNA), functions as a molecular scaffold to link and target the histone modification complexes PRC2 and LSD1, then reprograms chromatin states by coupling histone H3K27 methylation and H3K4 demethylation for epigenetic gene silencing to promote cancer metastasis. It is associated with poor survival in several solid cancers. In this study, we show that HOTAIR expression increased in oral squamous cell carcinoma (OSCC) compared with non-tumor tissue and is associated with metastasis, the stage and histological differentiation. In addition, overexpression of HOTAIR indicated poor overall survival (OS) and disease-free survival (DFS) in OSCC patients. Knockdown of HOTAIR by siRNA in OSCC cells decreased cell proliferation and colony formation, increased cell invasion and migration, and induced apoptosis in vitro. Furthermore, significant negative correlation between HOTAIR levels and E-cadherin levels was found in OSCC tissues and cell lines, and HOTAIR contributed to the regulation of E-cadherin through binding to EZH2 and H3K27me3 with the E-cadherin promoter. Our findings suggest that HOTAIR expression is associated with OSCC and may be one of critical targets in progression and metastasis, and an indicator of poor survival in OSCC.

Aims: We showed that chronic cholestatic liver injury induced the expression of c-Myc but suppressed that of glutamate-cysteine ligase (GCL, composed of catalytic and modifier subunits GCLC and GCLM, respectively). This was associated with reduced nuclear antioxidant response element (ARE) binding by nuclear factorerythroid 2 related factor 2 (Nrf2). Here, we examined whether c-Myc is involved in this process. Results: Similar to bile duct ligation (BDL), lithocholic acid (LCA) treatment in vivo induced c-Myc but suppressed GCL subunits expression at day 14. Nrf2 expression and Nrf2 ARE binding fell markedly. However, Nrf2 heterodimerization with MafG was enhanced by LCA, which prompted us to examine whether LCA treatment in vivo altered proteins that bind to ARE using biotinylated ARE in pull-down assay followed by proteomics. LCA treatment enhanced c-Myc but lowered prohibitin 1 (PHB1) binding to ARE. This was a result of c-Mycmediated induction of microRNA 27a/b (miR27a/b), which target both PHB1 and Nrf2 to reduce their expression. Knockdown of c-Myc or miR27a/b attenuated LCA-mediated suppression of Nrf2, PHB1, and GCL subunit expression, whereas overexpression of PHB1 protected against the fall in Nrf2 and GCL subunits. Both c-Myc and PHB1 directly interact with Nrf2 but c-Myc lowers Nrf2 binding to ARE while PHB1 enhances it. Innovation: This is the first work that shows how activation of this circuit in cholestatic liver injury inhibits GCL expression. Conclusions: LCA feeding and BDL activate c-Myc-miR27a/b-PHB1 circuit, with the consequence of inhibiting Nrf2 expression and ARE binding, resulting in decreased reduced glutathione synthesis and antioxidant capacity. Antioxid. Redox Signal. 22,[259][260][261][262][263][264][265][266][267][268][269][270][271][272][273][274]

Hedgehog signaling pathway plays an important role in normal mammalian gastrointestinal development and is implicated in the oncogenesis of various tumors. However, its correlation with progression and prognosis of colon cancer has not been well documented. This study was designed to investigate expression patterns of related proteins in hedgehog signaling pathway in colon cancer to elucidate its prognostic value in this tumor. Using human colon cancer and their corresponding non-diseased colon from 228 patients' biopsies, the expression of sonic hedgehog, its receptor Patched, and downstream transcription factor Gli1 was investigated by immunohistochemical staining to assess their association with the clinicopathological characteristics of colon cancer. Disease-free survival and overall survival were examined by Kaplan-Meier estimates and the log-rank test. Prognostic factors were determined by multivariate Cox analysis. One hundred and thirty-eight patients (59.6%) had sonic hedgehog-positive tumors and that the disease-free survival (43.5 vs. 73.3%, P < 0.001), and overall survival rates (50.7 vs. 88.9%, P < 0.001) of patients with sonic hedgehog-positive tumors were much lower than those of patients with sonic hedgehog-negative tumors. In addition, 163 patients (71.5%) had Patched-positive tumors, and the disease-free survival (41.7 vs. 76.9%, P < 0.001) and overall survival rates (55.2 vs. 80.0%, P = 0.002) of patients with Patched-positive tumors were also lower than those of patients with Patched-negative tumors. Moreover, positive Gli1 expression had a bad effect on the disease-free survival (41.9 vs. 73.2%, P < 0.001) and overall survival rate of patients with colon cancer (50.0 vs. 89.3%, P < 0.001). In a multivariate analysis, sonic hedgehog, Patched, and Gli1 status were indicators for poor disease-free survival and overall survival. These results have shown that the increasing expression of sonic hedgehog, Patched, and Gli1 are indicators for a poor prognosis in patients with colon cancer. This is the first report describing about the relationship between hedgehog signaling pathway and the prognosis of colon cancer.

Background Approximately 30% of patients with epidermal growth factor receptor (EGFR)-activating mutations have no response to EGFR-tyrosine kinase inhibitors (TKIs) (primary resistance). However, little is known about the molecular mechanism involved in primary resistance to EGFR-TKIs in EGFR-mutant non-small cell lung cancer (NSCLC). Programmed death ligand-1 (PD-L1) plays important regulatory roles in intracellular functions and leads to acquired resistance to EGFR-TKIs in NSCLC. Here, we investigated the mechanistic role of PD-L1 in primary resistance to EGFR-TKIs in EGFR-mutant NSCLC cells. Methods The expression levels of PD-L1 and the sensitivity to gefitinib in H1975, HCC827 and PC-9 cells were determined by quantitative real-time PCR analysis (qRT-PCR) and Cell Counting Kit-8 (CCK-8) assays, respectively. Molecular manipulations (silencing or overexpression) were performed to assess the effect of PD-L1 on sensitivity to gefitinib, and a mouse xenograft model was used for in vivo confirmation. Western blotting and qRT-PCR were used to analyse the expression of epithelial-mesenchymal transition (EMT) markers. The effect of PD-L1 on migratory and invasive abilities was evaluated using the Transwell assay and mice tail intravenous injection. Results Higher expression of PD-L1 was related to less sensitivity to gefitinib in EGFR-mutant NSCLC cell lines. The overexpression or knockdown of PD-L1 presented diametrical sensitivity to gefitinib in vitro and in vivo. Furthermore, the overexpression of PD-L1 led to primary resistance to gefitinib through the induction of EMT, which was dependent on the upregulation of Smad3 phosphorylation. Moreover, in the mouse model, the knockdown of PD-L1 inhibited transforming growth factor (TGF)-β1-induced cell metastasis in vivo. Conclusion PD-L1 contributes to primary resistance to EGFR-TKI in EGFR-mutant NSCLC cells, which may be mediated through the induction of EMT via the activation of the TGF-β/Smad canonical signalling pathway.