Hyaluronan (HA), a major component of the extracellular matrix (ECM), is enriched in many types of tumors. There is good evidence linking high levels of HA production in human carcinomas to an aggressive phenotype and tumor metastasis. HA is generally bound to CD44 isoforms (so-called CD44s and CD44v3) which are ubiquitous, abundant, and functionally important cell surface receptors. This chapter describes the evidence for HA/CD44v3-mediated activation of the cytoskeleton (e.g., ankyrin and GTPases) and matrix metalloproteinase (MMP) signaling during tumor progression. A special focus is placed on the role of HA–CD44v3 interaction in cancer stem cells (CSCs). Matrix HA is known to be present in CSC niches. Since CD44v3 serves as a CSC marker, it provides an important physical linkage between matrix HA and various transcription factors that regulate tumor cell functions through distinct signaling pathways. CSCs are known to be chemoresistant and/or radiation resistant and to cause cancer relapse. The purpose of this chapter is to review the most current research on the cellular and molecular biology of CSCs. The emphasis will be placed on both CSC niche and matrix HA-induced microRNA signaling plus various CSC functions (e.g., self-renewal, differentiation, and chemoresistance) during cancer progression. Understanding the regulation of CSCs is critically important for designing CSC-specific therapeutic targets to prevent cancer development and progression.

This study aims to investigate the role of miR-203-HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, KLF4 and nanog (stemness-markers) was also observed. This is the first report demonstrating miR-203 mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis.

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 upregulated by HA in CSCs (isolated from HSC-3 cells). Further analyses indicate that the stimulation of microRNA-10b (miR10b) 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 upregulation 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.Human head and neck squamous cell carcinoma (HNSCC) 2 is a highly malignant cancer associated with major morbidity and mortality (1). A number of studies have identified specific molecules expressed in HNSCC that correlate with tumor behavior. Among such molecules are matrix hyaluronan (HA) (2, 3) and its cell surface receptor, CD44 (4). HA is a major component of the ECM and is significantly enriched in many types of tumors (5). CD44 is a multifunctional transmembrane glycoprotein expressed in HNSCC cells and carcinoma tissues (6, 7). It is commonly expressed as various isoforms generated by alternative mRNA splicing of variant exons inserted into an extracellular membrane-proximal site (8). Most importantly, expression of certain CD44 variant (CD44v) isoforms (especially, CD44v3) is known to be associated with HNSCC progression (6, 9, 10).HNSCC appears to contain a subpopulation of cancer stem cells (CSCs) characterized by a high level of CD44v3 expression (10). In fact, CD44v3 is thought to be one of the important cell surface markers for CSCs (10). These isolated CSCs are capable of generating phenotypically distinct cells resulting in heteroge...

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.