Abstract
Tumor malignancies involve cancer cell growth, issue invasion, metastasis and often drug resistance. A great deal of effort has been placed on searching for unique molecule(s) overexpressed in cancer cells that correlate(s) with tumor cell-specific behaviors. Hyaluronan (HA), one of the major ECM (extracellular matrix) components have been identified as a physiological ligand for surface CD44 isoforms which are frequently overexpressed in malignant tumor cells during cancer progression. The binding interaction between HA and CD44 isoforms often stimulates aberrant cellular signaling processes and appears to be responsible for the induction of multiple oncogenic events required for cancer-specific phenotypes and behaviors. In recent years, both microRNAs (miRNAs) (with ~20–25 nucleotides) and long non-coding RNAs (lncRNAs) (with ~200 nucleotides) have been found to be abnormally expressed in cancer cells and actively participate in numerous oncogenic signaling events needed for tumor cell-specific functions. In this review, I plan to place a special emphasis on HA/CD44-induced signaling pathways and the presence of several novel miRNAs (e.g., miR-10b/miR-302/miR-21) and lncRNAs (e.g., UCA1) together with their target functions (e.g., tumor cell migration, invasion, and chemoresistance) during cancer development and progression. I believe that important information can be obtained from these studies on HA/CD44-activated miRNAs and lncRNA that may be very valuable for the future development of innovative therapeutic drugs for the treatment of matrix HA/CD44-mediated cancers.
Highlights
Cancer cells are known to display dysregulated signaling pathways which are responsible for abnormal cellular functions [1,2,3]
We have found that inhibition of JNK/c-Juninduced miR-21 signaling by various signaling perturbation agents such as JNK inhibitor or c-Jun siRNA or anti-miR-21 inhibitor effectively downregulates the expression of survival proteins such as Bcl2 and inhibitors of apoptosis proteins (IAPs) family of proteins leading to apoptosis/cell death and chemosensitivity
Targeting CD44 using anti-CD44 and/or CD44 variant-specific antibody and/or anti-sense strategies to downregulate CD44 and/or CD44 variants may be a possible choice for the development of new cancer cell-based therapies
Summary
Cancer cells are known to display dysregulated signaling pathways which are responsible for abnormal cellular functions [1,2,3]. Result in downregulation of survival proteins (e.g., cIAP-1, cIAP2, and XIAP) and upregulation of PDCD4 leading to tumor cell apoptosis/death and chemosensitivity in head and neck cancer [19, 65,66,67] This newly-discovered Nanog-Stat-3-regulated miR-21 signaling pathways during HA-CD44 interaction may be considered as another new drug target to treat cancers. HACD44-activated miR-302 has been shown to cause DNMT1 reduction and DNA demethylation in CD44v3-expressing cancer stem cells (CSCs) [31] This DNA demethylation process regulated by HA-CD44-activated miR-302 can activate the expression of several Inhibitor of Apoptosis Protein (IAP) family of proteins such as c-IAP1, c-IAP2, and XIAP which appear to be closely linked to several important activities unique for cancer stem cells (CSCs) isolated from head and neck caner [31] (Figure 3B).
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