Tumor microenvironment and noncoding RNAs as co‐drivers of epithelial–mesenchymal transition and cancer metastasis

Abstract

Reciprocal interactions between cancer cells and tumor microenvironment (TME) are crucial events in tumor progression and metastasis. Pervasive stromal reprogramming of TME modifies numerous cellular functions, including extracellular matrix (ECM) stiffness, inflammation, and immunity. These environmental factors allow selection of more aggressive cells that develop adaptive strategies associating plasticity and epithelial-mesenchymal transition (EMT), stem-like phenotype, invasion, immunosuppression, and resistance to therapies. EMT is a morphomolecular process that endows epithelial tumor cells with mesenchymal properties, including reduced adhesion and increased motility. Numerous studies have demonstrated involvement of noncoding RNAs (ncRNAs), such as miRNAs and lncRNAs, in tumor initiation, progression, and metastasis. NcRNAs regulate every hallmark of cancer and have now emerged as new players in induction and regulation of EMT. The reciprocal regulatory interactions between ncRNAs, TME components, and cancer cells increase the complexity of gene expression and protein translation in cancer. Thus, deeper understanding of molecular mechanisms controlling EMT will not only shed light on metastatic processes of cancer cells, but enhance development of new therapies targeting metastasis. In this review, we will provide recent findings on the role of known ncRNAs relevant to EMT and cancer metastasis and discuss the role of the interaction between ncRNAs and TME as co-drivers of EMT. Developmental Dynamics 247:405-431, 2018. V C 2017 Wiley Periodicals, Inc.

lncRNA ZEB1-AS1 inhibits high glucose-induced EMT and fibrogenesis by regulating the miR-216a-5p/BMP7 axis in diabetic nephropathy

“…Increased ECM deposition leads to renal fibrosis. It has been reported that noncoding RNAs (ncRNAs) are new participants in the induction and regulation of EMT and kidney fibrosis (9,10). Therefore, it is meaningful to explore the roles of ncRNAs in the molecular mechanisms of EMT and fibrosis.…”

NKILA inhibits NF-κB signaling and suppresses tumor metastasis

“…Aberrant activation of NF-κB underlies various human disorders including cancer [ 13 ], and has become one of the major targets for drug development [ 14 , 15 ]. For instance, siRNA mediated disruption of NF-κB significantly suppressed migration and invasion of ESCC cells though attenuation of the epithelial mesenchymal transition (EMT) [ 16 ], the initial step for tumor metastasis [ 17 ]. Recently, a long non-coding RNA (lncRNA) NKILA (nuclear transcription factor NF-κB interacting lncRNA) which could mask the phosphorylation site of IκB, inactivate the NF-κB signaling and suppress breast cancer metastasis [ 18 ] has attracted our attention.…”

Significance of Tumor Microenvironment Scoring and Immune Biomarkers in Patient Stratification and Cancer Outcomes

“…ECM selects survival cancer cells to aid in tumor growth and invasion at the fastest rate. ECM can also affect tumor development and metastasis through extracellular secretion, or by altering the phenotype of stromal cells or cancer cells [3].…”

“…Within this dynamic space, exchange of numerous molecular information is associated with the transition into tumorigenic microenvironment and includes growth factors (GFs), cytokines, chemokines, enzymes, matrix proteins, and metabolic intermediates. Recruitment, activation, reprogramming, and persistence of stromal and immune/inflammatory cells in the extracellular space are the consequences of a reciprocal interaction between TME and cancer cells [2,3].…”