Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression

Abstract

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 linked to tumor cell properties. One of the candidates is matrix hyaluronan (HA), which is known as one of the major extracellular matrix (ECM) components. HA serves as a physiological ligand for surface CD44 molecule and also functions as a bio-regulator. The binding of HA to CD44 has been shown to stimulate concomitant activation of a number of oncogenic pathways and abnormal cellular processes in cancer cells and cancer stem cells (CSCs). MicroRNAs (miRNAs) belong to a class of small RNAs containing ~20-25 nucleotides and are known to promote aberrant cellular functions in cancer cells. In this article, I have focused on the role of HA interaction with CD44 and several important signaling molecules in the regulation of unique miRNAs (e.g., miR-21, miR-302 and miR-10b) and their downstream targets leading to multiple tumor cell-specific functions (e.g., tumor cell growth, drug resistance and metastasis) and cancer progression. This new knowledge could provide the groundwork necessary for establishing new tumor markers and developing important, novel drugs targeted against HA/CD44-associated tumor progression, which can be utilized in the therapeutic treatment of metastatic cancer patients.

Keywords: CD44; cancer stem cells (CSCs); chemoresistance; hyaluronan (HA); microRNA (miRNA); signaling; tumor progression.

Figure 1

Illustration of the structure of hyaluronan (HA).

Figure 2

Illustration of CD44 gene and alternative spliced variants (CD44v isoforms). The HA binding domain is located at the external (in particular, N-terminal) region of CD44 and the signaling regulators’ binding sites are located at the cytoplasmic domain of CD44.

Figure 3

PKCϵ and JNK (c-Jun-NH2-Kinase) Signaling Pathways in Regulating HA/CD44-mediated miR-21 expression leading to chemoresistance: In the PKCϵ signaling pathway, HA binding to CD44 (step 1) stimulates PKCϵ activity (step 2), which, in turn, causes Nanog phosphorylation and Nanog-Stat-3 complex association with miR-21 promoter (step 3) leading to transcriptional activation (step 4) and the expression of miR-21 (step 5). Upregulation of miR-21 then decreases the expression of the tumor suppressor protein, PDCD4 (step 6) and increases the expression of IAP (survivin and XIAP)/MDR1 (P-gp), tumor cell anti-apoptosis/survival, and chemoresistance (step 7). All these events are required for cancer progression. In the JNK/c-Jun pathway, the binding of HA to CD44 (step 1) stimulates JNK and c-Jun phosphorylation (step 2). Subsequently, phosphorylated c-Jun binds to the miR-21 promoter (step 3), resulting in transcriptional activation (step 4) and mature miR-21 production (step 5). Upregulation of miR-21 then reduces the tumor suppressor protein, PDCD4 (step 6) and increases the expression of the survival proteins (e.g., Bcl2, c-IAP-1, c-IAP-2 and XIAP) (step 7), anti-apoptosis/survival and chemo resistance. All these events are needed for cancer progression.

Figure 4

HA-CD44 interaction promotes miRNA-302 expression and chemoresistance: In cancer stem cell (CSC) signaling, the binding of HA to CD44 (step 1) stimulates Nanog, Oct4, and Sox2 complex formation with CD44v3 (step 2). This Nanog-Oct4-Sox2 signaling complex then interacts with the promoter region (containing Nanog, Oct4 and Sox2-binding sites) of the miR-302 cluster (step 3) resulting in miR-302 cluster gene expression (step 4) and mature miR-302a and miR-302b production (step 5). The resultant miR-302 then downregulates the lysine-specific histone demethylases (namely AOF1 and AOF2) and DNA (cytosine-5)-methyltransferase 1 (DNMT1) (step 6) and induces global DNA demethylation (step 7) leading to IAP (cIAP-1, cIAP-2, and XIAP) expression, self-renewal, clonal formation, anti-apoptosis/survival, and chemoresistance in CSC-like CD44v3^highALDH1^high cells. All these events participate in cancer progression.

Figure 5

HA-CD44 interaction promotes c-Src and Twist activation and miR-10b expression during tumor cell migration/invasion and chemoresistance: In the c-Src-Twist signaling pathway, HA binding to CD44 (step 1) activates c-Src kinase (step 2), which, in turn, induces Twist phosphorylation (step 3). Phosphorylated Twist then binds to the E-box elements of the mR-10b promoter (step 4), causing transcriptional activation (step 5) and miR-10b expression (step 6). The upregulation of miR-10b then reduces the expression of HOXD10 (the tumor suppressor protein) (step 7) and enhances RhoA/RhoC upregulation and ROK activation, as well as cytoskeleton reorganization) leading to tumor metastasis and cancer progression.