Multidrug resistance frequently contributes to the failure of chemotherapeutic drug treatments in patients diagnosed with solid tumors such as breast, ovarian and head and neck cancers. It is now certain that oncogenic signaling is directly involved in chemotherapeutic drug resistance and tumor progression. A number of studies have aimed at identifying those molecules which are expressed specifically by epithelial tumor cells and correlate with metastatic behavior and chemotherapy resistance. Among such candidate molecules is hyaluronan (HA), the major glycosaminoglycan component of extracellular matrix (ECM). HA serves not only as a primary constituent of connective tissue extracellular matrices but also functions as a bio-regulatory molecule. Pertinently, HA is enriched in many types of tumors. HA is capable of binding to CD44 which is a ubiquitous, abundant and functionally important receptor expressed on the surface of many normal cells and tumor cells.
Recent evidence indicates that HA-CD44 interaction with the stem cell marker, Nanog promotes downstream, intracellular signaling pathways that influence multiple cellular functions. In particular, certain microRNAs such as miR-21 (small RNA molecules with ∼20–25 nucleotides) have been shown to play roles in regulating tumor cell survival and chemotherapy resistance. In this article, a special focus is placed on the role of Nanog overexpression in activating oncogenic signaling molecule(s) and miRNA-21 function leading to the concomitant onset of HA/CD44-mediated tumor cell activities (e.g., survival and chemoresistance) and tumor progression. Conversely, donwregulation of Nanog not only inhibits miR-21 expression/function and HA/CD44-mediated tumor cell behaviors but also enhances chemosensitivity. This new knowledge could serve as groundwork for the future development of new drug targets to inhibit the stem cell marker (Nanog) signaling and miR-21 function in order to overcome chemotherapy resistance in the progression of HA/CD44-induced solid tumor cancers such as breast, ovarian and head and neck cancer.
Ovarian Cancer Stem Cell Marker Breast Tumor Cell Epithelial Tumor Cell Ovarian Tumor Cell
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