Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma.

Lung adenocarcinoma (LAD) is a human malignancy successfully treated with the tyrosine kinase inhibitor (TKI) gefitinib; however, the enrichment of therapy resistant cancer stem cells (CSCs) in such patients is assumed to be a source of treatment failure. Evaluation of LAD cell populations treated with the TKI inhibitor gefitinib identified unique aspects of a subpopulation of tumor cells exhibiting stem-like properties and mitochondria-specific metabolic features along with their reliance on sirtuin 1 (SIRT1) for survival advantage. This addiction to bioenergetic metabolism in LAD treated with EGFR-targeted therapy suggests that mitochondrial targeting should be synthetically lethal using established cytotoxic therapies. Accordingly, loss of the phenotype present in resistant CSC clones either by targeting the energy metabolism with tigecycline, a mitochondrial DNA-translation inhibitor, or tenovin-6 (TV-6), a SIRT1 inhibitor, inhibited their dependency on mitochondrial oxidative phosphorylation (mtOXPHOS) and sensitized them for a more pronounced and long-lasting TKI therapeutic effect. The results specifically demonstrated that combined therapy with TV-6 and gefitinib resulted in tumor regression in xenograft mouse models, whereas administration of a single agent showed no such efficacy. Importantly, combined treatment with TV-6 also decreased the effective dose of gefitinib necessary for treatment response. Clinical analysis demonstrated that high-profile SIRT1 and mtOXPHOS proteins were associated with recurrence and poor prognosis in LAD patients. These observations support the CSC hypothesis for cancer relapse and advocate use of mitochondria-targeting inhibitors as part of combinatorial therapy in a variety of clinical settings, as well as for reducing first-line TKI dosage in LAD patients.

Long noncoding RNA CASC11 promotes osteosarcoma metastasis by suppressing degradation of snail mRNA.

Osteosarcoma (OS) is the most common primary bone tumor in adolescents. Dysregulation of long noncoding RNAs (lncRNAs) is associated with the cancer progression, of which cancer susceptibility candidate 11 (CASC11) has been indicated as an oncogene in several human cancers. However, the underlying mechanisms by which CASC11 contributes to OS metastasis remain undetermined. Here, we found that CASC11 expression in OS tissues was markedly higher than that in noncancerous tissues. Clinical association analysis revealed that high CASC11 expression correlated with clinical stage, distant metastasis and poor prognosis of OS patients. Gain- and loss-of-function assays demonstrated that CASC11 promoted migration, invasion, epithelial-mesenchymal transition (EMT) and metastasis of OS cells in vitro and in vivo. CASC11 associated with the EMT inducer Snail mRNA and increased its stability. Association of CASC11 with Snail mRNA blocked the repressing effect of miR-122, miR-145, miR-211, miR-34a and miR-137 on Snail. Moreover, CASC11-specific siRNAs significantly inhibit tumor metastasis in vivo. Taken together, our findings suggest that CASC11 may be a candidate prognostic biomarker and a novel therapeutic target for OS.

MicroRNA-367 is a potential diagnostic biomarker for patients with esophageal squamous cell carcinoma.

PURPOSE: In this study, we investigated whether microRNA-367 (miR-367) may serve as a circulating biomarker and tumor oncogene in esophageal squamous carcinoma (ESCC). METHODS: Circulating serum miR-367 was compared by quantitative RT-PCR (qRT-PCR) between 35 ESCC patients and 35 normal control patients, as well paired ESCC tumor tissues and adjacent non-tumor esophageal epithelial tissues in 46 patients. The correlation between serum miR-367 and clinicopathological properties of ESCC patients was assessed. The overall survival (OS) was assessed by Kaplan-Meier method and compared by log-rank test between patients with high serum miR-367 and low serum miR-367. The possibility of miR-367 being independent prognostic factor for ESCC was also assessed. Furthermore, lentivirus-mediated miR-367 downregulation was conducted in ESCC cell lines Kyse30 and TE-1 cells to assess the possible oncogenic effect of miR-367 on ESCC proliferation and cell cycle transition in vitro. RESULTS: MiR-367 was aberrantly upregulated in sera and tumors of ESCC patients, whereas downregulated in ESCC patients after the treatments of esophagectomy and chemotherapy. Serum miR-367 was found to be closely correlated with the clinicopathological properties of differentiation grades, clinical stage and tumor metastasis in ESCC patients. Serum miR-367 was also confirmed to be associated with OS, as well as serving independent prognostic factor in ESCC patients. Moreover, lentivirus-induced miR-367 downregulation inhibited cancer growth and cell cycle transition in Kyse30 and TE-1 cells. CONCLUSION: MiR-367 is a potential biomarker for ESCC and may act as an oncogene in regulating ESCC development.