Cisplatin and paclitaxel resistance is associated with CTSL upregulation-induced EMT in A549 cells. Thus, CTSL-mediated EMT may be exploited as a target to enhance the efficacy of cisplatin or paclitaxel against lung cancer and other types of malignancies.

An increasing number of reports have revealed that long non-coding RNAs are important players in tumorigenesis. Here we showed that long non-coding RNA LINC00461 is highly expressed in glioma tissues compared to non-neoplastic brain tissues. The knockdown of LINC00461 suppressed cyclinD1/A/E expression which led to G0/G1 cell cycle arrest and inhibited cell proliferation in glioma cells. LINC00461 suppression also inhibited glioma cell migration and invasion. The function of LINC00461 in glioma cells is partially mediated by MAPK/ERK and PI3K/AKT signaling pathways as down-regulation of LINC00461 expression suppressed ERK1/2 and AKT activities. Moreover, LINC00461 knockdown decreased expression levels of microRNA miR-9 and flanking genes MEF2C and TMEM161B. Taken together, our results demonstrate that LINC00461 is important for glioma progression affecting cell proliferation, migration and invasion via MAPK/ERK, PI3K/AKT, and possibly other signaling pathways.

BackgroundIonizing radiation (IR) is one of the major clinical therapies of cancer, although it increases the epithelial-mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC), unexpectedly. The cellular and molecular mechanisms underlying this role are not completely understood.MethodsWe used NSCLC cell lines as well as tumor specimens from 78 patients with NSCLC to evaluate p53, Cathepsin L (CTSL) and EMT phenotypic changes. Xenograft models was also utilized to examine the roles of mutant p53 (mut-p53) and CTSL in regulating IR-induced EMT of NSCLC.ResultsExpression of CTSL was markedly increased in human NSCLC tissues with mutant p53 (mut-p53), and p53 mutation positively correlated with metastasis of NSCLC patients. In human non-small cell lung cancer cell line, H1299 cells transfected with various p53 lentivirus vectors, mut-p53 could promote the invasion and motility of cells under IR, mainly through the EMT. This EMT process was induced by elevating intranuclear CTSL which was regulated by mut-p53 depending on Early growth response protein-1 (Egr-1) activation. In the subcutaneous tumor xenograft model, IR promoted the EMT of the cancer cells in the presence of mut-p53, owing to increase expression and nuclear transition of its downstream protein CTSL.ConclusionTaken together, these data reveal the role of the mut-p53/Egr-1/CTSL axis in regulating the signaling pathway responsible for IR-induced EMT.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1054-x) contains supplementary material, which is available to authorized users.

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Cathepsin L (CTSL), a cysteine protease, is closely related to tumor occurrence, development, and metastasis, and possibly regulates cancer cell resistance to chemotherapy. miRNAs, especially the miR-200 family, have been implicated in drug-resistant tumors. In this study we explored the relationship of CTSL, miRNA-200c and drug resistance, and the potential regulatory mechanisms in human lung cancer A549 cells and A549/TAX cells in vitro. A549/TAX cells were paclitaxel-resistant A549 cells overexpressing CTSL and characterized by epithelial-mesenchymal transition (EMT). We showed that miRNA-200c and CTSL were reciprocally linked in a feedback loop in these cancer cells. Overexpression of miRNA-200c in A549/TAX cells decreased the expression of CTSL, and enhanced their sensitivity to paclitaxel and suppressed EMT, whereas knockdown of miRNA-200c in A549 cells significantly increased the expression of CTSL, and decreased their sensitivity to paclitaxel and induced EMT. Overexpression of CTSL in A549 cells significantly decreased the expression of miRNA-200c, and reduced their sensitivity to paclitaxel and induced EMT, but these effects were reversed by miRNA-200c, whereas knockdown of CTSL in A549/TAX cells attenuated paclitaxel resistance and remarkably inhibited EMT, but the inhibition of miRNA-200c could reverse these effects. Therefore, miRNA-200c may be involved in regulating paclitaxel resistance through CTSL-mediated EMT in A549 cells, and CTSL and miRNA-200c are reciprocally linked in a feedback loop.