Wnt signaling through Snail1 and Zeb1 regulates bone metastasis in lung cancer

Wnt-β-catenin signaling participates in the epithelial-mesenchymal transition (EMT) in a variety of cancers; however, its role in lung cancer induced bone metastasis and the underlying mechanisms remain unclear. Here, we demonstrate that β-catenin, Snail1 and Zeb1 were significantly upregulated in bone metastasis tissues from human and mouse compared with the normal controls. E-cadherin expression is negatively regulated by Zeb1, Snail1 and β-catenin during bone metastasis tissues induced by lung cancer. Knocking down Zeb1 and Snail1 in lung cancer cell lines showed increased E-cadherin mRNA expression and less invasion compared with the original cell lines. In addition, β-catenin knockdown led to the increase of E-cadherin and the decrease of Zeb1 and Snail1, which in turn inhibited the invasive properties of lung cancer. Our results demonstrated that Wnt signaling through Snail1 and Zeb1 regulates bone metastasis in lung cancer.     

Plasma miR‐122 and miR‐200 family are prognostic markers in colorectal cancer

Circulating microRNAs (miRNAs) have been proposed as minimally invasive prognostic markers for various types of cancers, including colorectal cancer (CRC), the third most diagnosed cancer worldwide. We aimed to evaluate the levels of circulating miRNAs that might serve as markers for CRC prognosis and survival. We included plasma samples of 543 CRC patients with stage I‐IV disease from a population‐based study carried out in Germany. After comprehensive evaluation of current literature, 95 miRNAs were selected and measured with Custom TaqMan® Array MicroRNA Cards. Plasma samples of non‐metastatic and metastatic colon cancer patients, each group consisting of ten patients with ‘good’ and ten patients with ‘bad’ prognosis were screened. Identified candidate miRNAs were further validated by RT‐qPCR in the whole study cohort. The association of the miRNA levels with patients' survival and the prognostic subtypes was analyzed with uni‐ and multivariate logistic regression and Cox proportional hazards regression models. Increased miR‐122 levels were associated with a ‘bad’ prognostic subtype in metastatic CRC (Odds ratio: 1.563, 95% confidence interval (CI): 1.038‐2.347) and a shorter relapse‐free survival and overall survival for non‐metastatic (Hazard ratio (HR): 1.370, 95% CI: 1.028‐1.825; HR: 1.353, 95% CI: 1.002‐1.828) and metastatic (HR: 1.264, 95% CI: 1.050‐1.520; HR: 1.292, 95% CI: 1.078‐1.548) CRC patients. Additionally, several members of the miR‐200 family showed associations with patients' prognosis and correlations to clinicopathological characteristics. The here identified miRNA markers, miR‐122 and the miR‐200 family members, could be of use in the development of a multi‐marker blood test for CRC prognosis.     

MiR‐200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1

Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR‐200c in four distinct breast cancer cell lines: two representative basal cancer cells (MDA‐MB‐231 and BT549) vs. two representative luminal cancer cells (MCF‐7 and BT474). The results revealed practically lower expression of miR‐200c in the two basal cancer cell lines and higher expression of miR‐200c in luminal cancer cells compared to the normal breast epithelial cell line MCF‐10A. Ectopic expression of miR‐200c in MDA‐MB‐231 cells inhibited irradiation‐induced autophagy and sensitized the breast cancer cells to irradiation. We also identified UBQLN1 as a direct functional target of miR‐200c involved in irradiation‐induced autophagy and radioresistance. In 35 human breast cancer tissue samples, we detected an inverse correlation between the expression of miR‐200c vs. UBQLN1 and LC3. These results indicate that the identified miR‐200c/UBQLN1‐mediated autophagy pathway may help to elucidate radioresistance in human breast cancer and might represent a therapeutic strategy.     

miR‐20a inhibits hypoxia‐induced autophagy by targeting ATG5/FIP200 in colorectal cancer

Autophagy is a highly conserved lysosome‐mediated protective cellular process in which cytosolic components, including damaged organelles and long‐lived proteins, are cleared. Many studies have shown that autophagy was upregulated in hypoxic regions. However, the precise molecular mechanism of hypoxia‐induced autophagy in colorectal cancer (CRC) is still elusive. In this study, we found that miR‐20a was significantly downregulated under hypoxia in colon cancer cells, and overexpression of miR‐20a alleviated hypoxia‐induced autophagy. Moreover, miR‐20a inhibits the hypoxia‐induced autophagic flux by targeting multiple key regulators of autophagy, including ATG5 and FIP200. Furthermore, by dual‐luciferase assay we demonstrated that miR‐20a directly targeted the 3′‐untranslated region of ATG5 and FIP200, regulating their messenger RNA and protein levels. In addition, reintroduction of exogenous ATG5 or FIP200 partially reversed miR‐20a‐mediated autophagy inhibition under hypoxia. A negative correlation between miR‐20a and its target genes is observed in the hypoxic region of colon cancer tissues. Taken together, our findings suggest that hypoxia‐mediated autophagy was regulated by miR‐20a/ATG5/FI200 signaling pathway in CRC. miR‐20a‐mediated autophagy defect that might play an important role in hypoxia‐induced autophagy during colorectal tumorigenesis.