Long Noncoding RNA MALAT-1 Enhances Stem Cell-Like Phenotypes in Pancreatic Cancer Cells

Laboratory Investigation

Helein

et al. 2017

The cancer stem-like cell (CSC) hypothesis postulates that a small population of cells in a cancer has self-renewal and clonal tumor initiation properties. These cells are responsible for tumor initiation, growth, recurrence and for resistance to chemotherapy and radiation therapy. CSCs can be characterized using markers such as SSEA-1, SSEA-4, CD44, CD24, ALDEFLUOR and others. CSCs form spheres when they are cultured in serum-free condition in low attachment plates and can generate tumors when injected into immune-deficient mice. During epithelial to mesenchymal transition (EMT), cells lose cellular adhesion and polarity and acquire an invasive phenotype. Recent studies have established a relationship between EMT and increased numbers of CSCs in some solid malignancies. Non-coding RNAs such as microRNAs and long non-coding RNAs (lncRNAs) have been shown to have important roles during EMT and some of these molecules also have regulatory roles in the proliferation of CSCs. Specific lncRNAs enhanced cell migration and invasion in breast carcinomas, which was associated with the generation of stem cell properties. The tumor microenvironment of CSCs also has an important role in tumor progression. Recent studies have shown that the interaction between tumor cells and the local microenvironment at the metastatic site leads to the development of premetastatic niche(s) and allows for the proliferation of the metastatic cells during colonization. The role of exosomes in the microenvironment during the EMT program is currently a major area of research. This review examines CSCs and the relationship between EMT and CSCs in solid tumors with emphasis on thyroid CSCs. The role of non-coding RNAs and of the microenvironment in EMT and in tumor progression are also examined. This review also highlights the growing number of studies that show the close association of EMT and CSCs and the role of exosomes and other elements of the tissue microenvironment in CSC metastasis. A better understanding of these mechanisms will lead to more effective targeting of primary and metastatic malignancies.

Section: Metastasis-associated Lung Adenocarcinoma Transcript 1 (Malat1)mentioning

confidence: 99%

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

Hardin

Laboratory Investigation

Helein

et al. 2017

“…Various lncRNAs, such as HOTTIP, MEG3, UCA1 and MALAT1, have been demonstrated to be involved in different carcinomas including MM [9]. MicroRNAs are critical members of non-coding RNAs (ncRNAs), which are 22 nucleotides in length.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of Linc00515 Inhibits Multiple Myeloma Autophagy and Chemoresistance by Upregulating miR-140-5p and Downregulating ATG14

Yang

et al. 2018

Cell Physiol Biochem

Background/Aims: The purpose of our experiments was to investigate the targeting relationship of linc00515, miR-140-5p and ATG14 and to explore the roles of linc00515, miR-140-5p and ATG14 in autophagy and chemoresistance of melphalan-resistant multiple myeloma cells. Methods: Plasmids that could interfere with the expression of linc00515 and ATG14 were loaded into myeloma cells, which were cultured with melphalan. MTT assay and flow cytometry analysis were utilized to investigate the effect of linc00515, miR-140-5p and ATG14 on the resistance of myeloma cells. QRT-PCR was used to determine the levels of mRNAs. Western blot was utilized to explore the level of ATG14 and autophagy-related proteins. Dual luciferase assay was utilized to explore the targeting relationship between linc00515, miR-140-5p and ATG14. GFP LC3 fluorescence assay was conducted to study the autophagy of cells. Results: The expression of linc00515 and ATG14 were significantly higher in melphalan-resistant myeloma cells. Knockdown of linc00515 and ATG14 led to decreased autophagy and chemoresistance of melphalan-resistant myeloma cells. The forced expression of miR-140-5p suppressed autophagy and chemoresistance of melphalan-resistant myeloma cells. Conclusion: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

“…We also found aberrant expression of 1,733 mRNAs in A549/PTX cells compared with the parental A549 cells. Various of the differentially expressed lncRNAs and mRNAs including, MALAT1, TUG1, HOTAIR, ABCB1 (MDR1) and Wnt6 have been previously reported in other chemoresistant cancers (23)(24)(25)(26)(27). Whether the molecular mechanisms of chemoresistance are the same as in the A549/PTX cells warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Microarray expression profile of long non-coding RNAs in paclitaxel-resistant human lung adenocarcinoma cells

Tian

et al. 2017

Oncology Reports

Abstract. Paclitaxel (PTX)-based chemotherapy is a standard treatment for human lung adenocarcinoma, but treatment often fails since resistance develops. Recent studies have described the activity of long non-coding RNAs (lncRNAs) in many biological processes and human diseases. Chemotherapy resistance is one of these areas, but the role of lncRNAs in paclitaxel resistance of human lung adenocarcinoma cells has not been reported. A paclitaxel resistance model was established using A549 human lung adenocarcinoma cells. lncRNAs and mRNAs were profiled in parental A549 and paclitaxel-resistant A549/PTX cells by microarray analysis. Real-time quantitative PCR (RT-qPCR) was used to validate the results of the microarray. Chromosomal distribution patterns of differentially expressed lncRNAs and mRNAs were assessed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using gene set enrichment. We screened 1,154 lncRNAs and 1,733 mRNAs that had a >3-fold difference in expression in A549/PTX cells compared with A549 cells, most of which were downregulated. Nine lncRNAs and six mRNAs were randomly selected and validated by RT-qPCR. Most aberrantly expressed lncRNAs and mRNAs were located on chromosomes 1, 2, 6, 12 and 17, particularly on chromosome 1. Bioinformatics, GO and KEGG pathway analyses, revealed that some differentially expressed genes regulated classical functions and pathways such as cytosol components, protein binding, gene expression and metabolic pathways. Differential expression of lncRNAs and mRNAs in A549/PTX and A549 cells indicates that various lncRNAs may be useful diagnostic or prognostic markers of resistance to treatment, or future targets for paclitaxel-based chemotherapy, providing a novel rationale for clinical treatment.