A hallmark of all solid tumor malignancies is the ability to invade the surrounding tissue and/or metastasize to distant sites. Tumors cells have altered signaling pathways which that to cytoskeleton activation and migration. Myriad studies have attempted to identify specific adhesion molecule(s) expressed in solid tumor cells that correlate with tumor cell migrative and invasive behaviors. 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. Several lines of evidence indicate that CD44 selects its unique downstream effectors and coordinates downstream, intracellular signaling pathways that influence multiple cellular functions. Certain microRNAs [(miRNAs), small RNA molecules with ~20-25 nucleotides] have been shown to play roles in regulating tumor cell migration, invasion, survival and chemotherapy resistance. In this article, a special focus is placed on the role of HA-mediated CD44 interaction with unique signaling molecules in activating intracellular miRNA-signaling and RhoGTPase functions leading to the concomitant onset of tumor cell activities (e.g., tumor cell migration, invasion, survival and chemoresistance) and tumor progression. This new knowledge could serve as groundwork for the future development of new drug targets to inhibit HA/CD44-mediated oncogenic signaling and cancer progression.

MicroRNA-21 (miR-21) is associated with the development of solid tumors progression including breast cancer. In this study we investigated matrix hyaluronan (HA)-CD44 (a primary HA receptor) interaction with c-Jun N-Terminal Kinase (JNK)/c-Jun signaling in MDA-MB-468 breast cancer cells [a triple-negative (estrogen receptor-negative/progesterone receptor-negative/HER2-negative) breast cancer cell line]. Our results indicated that HA binding to CD44 promotes c-Jun nuclear translocation and transcriptional activation. Further analyses revealed that miR-21 is regulated by an upstream promoter containing AP1 binding site(s), and chromatin immunoprecipitation (CHIP) assays demonstrated that stimulation of miR-21 expression by HA/CD44 interaction is c-Jun-dependent in these breast cancer cells. This process results in an increase of the anti-apoptosis protein Bcl-2 and upregulation of inhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in MDA-MB-468 cells. Treatment with c-Jun specific small interfering RNAs effectively blocks HA-mediated c-Jun signaling and abrogates miR-21 production as well as causes downregulation of survival proteins (Bcl-2 and IAPs) and enhancement of chemosensitivity. In addition, our results demonstrated that anti-miR-21 inhibitor not only downregulates Bcl-2/IAP expression but also increases chemosensitivity in HA-treated breast cancer cells. Together, these findings suggest that the HA/CD44-induced c-Jun signaling plays a pivotal role in miR-21 production leading to survival protein (Bcl-2/IAP) upregulation and chemoresistance in triple negative breast cancer cells such as MDA-MB-468 cell line. This novel HA/CD44-mediated c-Jun signaling pathway and miR-21 production provide a new drug target for the future intervention strategies to treat breast cancer.

Hyaluronan (HA), a major component of the extracellular matrix, is enriched in skin tissues, particularly the epidermis. HA binds to a ubiquitous, abundant, and functionally important family of cell surface receptors, CD44. This article reviews the current evidence for HA/CD44-mediated activation of RhoGTPase signaling and calcium mobilization, leading to the regulation of keratinocyte activities and various epidermal functions. It further discusses the role of HA-mediated CD44 interactions with unique downstream effectors, such as RhoGTPases (RhoA and Rac1), Rho-kinase, protein kinase-Nγ, and phosphoinositide-specific phospholipases (phospholipases Cε and Cγ1) in coordinating certain intracellular signaling pathways, such as calcium mobilization, phosphatidylinositol 3-kinase-AKT activation, cortactin-actin binding, and actin-associated cytoskeleton reorganization; generating the onset of important keratinocyte activities, such as cell adhesion, proliferation, migration, and differentiation; and performing epidermal functions. Topical application of selective HA fragments (large versus small HA) to the skin of wild-type mice (but not CD44 knockout mice) improves keratinocyte-associated epidermal functions and accelerates permeability barrier recovery and skin wound healing. Consequently, specific HA fragment (large versus small HA)-mediated signaling events (through the CD44 receptor) are required for keratinocyte activities, which offer new HA-based therapeutic options for patients experiencing epidermal dysfunction and skin damage as well as aging-related skin diseases, such as epidermal thinning (atrophy), permeability barrier dysfunction, and chronic nonhealing wounds.

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.

Solid tumor invasion, metastasis and therapeutic drug resistance are the common causes for serious morbidity and cancer recurrence in patients. A number of research studies have searched for malignancy-related biomarkers and drug targets that are closely l

© 2015 Bourguignon and Bikle.Hyaluronan (HA), the major extracellular matrix component, is often anchored to CD44, a family of structurally/functionally important cell surface receptors. Recent results indicate that UV irradiation (UVR)-induced cutaneous s

© 2015 Marisa Shiina and Lilly Y. W. Bourguignon.We determined that human head and neck cancer cells (HSC-3 cell line) contain a subpopulation displaying cancer stem cell (CSC) properties and are very tumorigenic. Specifically, we investigated whether diff

Head and neck squamous cell carcinoma (HNSCC) is a solid tumor composed by a genotypically and phenotypically heterogeneous population of neoplastic cells types. High recurrence rate and regional metastases lead to major morbidity and mortality. Recently, many studies have focused on cellular and molecular mechanisms of tumor progression that can help to predict prognosis and to choose the best therapeutic approach for HNSCC patients. Hyaluronan (HA), an important glycosaminoglycan component of the extracellular matrix (ECM), and its major cell surface receptor, CD44, have been suggested to be important cellular mediators influencing tumor progression and treatment resistance in head and neck cancer. HNSCC contains a small subpopulation of cells that exhibit a hallmark of CD44-expressing cancer stem cell (CSC) properties with self-renewal, multipotency, and a unique potential for tumor initiation. HA has been shown to stimulate a variety of CSC functions including self-renewal, clone formation and differentiation. This review article will present current evidence for the existence of a unique small population of CD44v3highALDHhigh-expressing CSCs in HNSCC. A special focus will be placed on the role of HA/CD44-induced oncogenic signaling and histone methyltransferase, DOT1L activities in regulating histone modifications (via epigenetic changes) and miRNA activation. Many of these events are essential for the CSC properties such as Nanog/Oct4/Sox2 expression, spheroid/clone formation, self-renewal, tumor cell migration/invasion, survival and chemotherapeutic drug resistance in HA-activated head and neck cancer. These newly-discovered HA/CD44-mediated oncogenic signaling pathways delineate unique tumor dynamics with implications for defining the drivers of HNSCC progression processes. Most importantly, the important knowledge obtained from HA/CD44-regulated CSC signaling and functional activation could provide new information regarding the design of novel drug targets to overcome current therapeutic drug resistance which will have significant treatment implications for head and neck cancer patients.

Human head and neck squamous cell carcinoma is a solid tumor malignancy associated with major morbidity and mortality. In this study, we determined that human head and neck squamous cell carcinoma-derived HSC-3 cells contain a subpopulation of cancer stem cells (CSCs) characterized by a high level of CD44v3 and aldehyde dehydrogenase-1 (ALDH1) expression. Importantly, matrix hyaluronan (HA) induces the up-regulation of stem cell markers that display the hallmark CSC properties. Histone methyltransferase, DOT1L, is also up-regulated by HA in CSCs (isolated from HSC-3 cells). Further analyses indicate that the stimulation of microRNA-10b (miR-10b) expression is DOT1L-specific and HA/CD44-dependent in CSCs. This process subsequently results in the overexpression of RhoGTPases and survival proteins leading to tumor cell invasion and cisplatin resistance. Treatment of CSCs with DOT1L-specific small interfering RNAs (siRNAs) effectively blocks HA/CD44-mediated expression of DOT1L, miR-10b production, and RhoGTPase/survival protein up-regulation as well as reduces tumor cell invasion and enhances chemosensitivity. CSCs were also transfected with a specific anti-miR-10b inhibitor to silence miR-10b expression and block its target functions. Our results demonstrate that the anti-miR-10 inhibitor not only decreases RhoGTPase/survival protein expression and tumor cell invasion, but also increases chemosensitivity in HA-treated CSCs. Taken together, these findings strongly support the contention that histone methyltransferase, DOT1L-associated epigenetic changes induced by HA play pivotal roles in miR-10 production leading to up-regulation of RhoGTPase and survival proteins. All of these events are critically important for the acquisition of cancer stem cell properties, including self-renewal, tumor cell invasion, and chemotherapy resistance in HA/CD44-activated head and neck cancer.

MicroRNA-21 (miR-21) is associated with the development of solid tumors progression including breast cancer. In this study we investigated matrix hyaluronan (HA)-CD44 (a primary HA receptor) interaction with c-Jun N-Terminal Kinase (JNK)/c-Jun signaling in