Hyaluronan-CD44v3 Interaction with Oct4-Sox2-Nanog Promotes miR-302 Expression Leading to Self-renewal, Clonal Formation, and Cisplatin Resistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Bourguignon, Lilly Y.W.; Wong, Gabriel; Earle, Christine; Chen, Liqun

doi:10.1074/jbc.m111.308528

Cited by 257 publications

(288 citation statements)

References 71 publications

(138 reference statements)

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“…These findings clearly indicate that these CSCs display the hallmark stem cell properties of self-renewal and the ability to generate heterogeneous cell populations. In addition, these CSCs display chemoresistance and thereby can cause recurrence of the cancers (10). However, information regarding CSC-mediated chemotherapy resistance and subsequent HNSCC development is very limited.…”

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confidence: 99%

“…In particular, certain miRNAs appear to play a critical role in various CSC functions and tumor progression (9,10). However, very little is known concerning the regulation of these miRNAs and their function in head and neck cancer.…”

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confidence: 99%

“…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 heterogeneous tumors in immunodeficient mice.…”

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confidence: 99%

“…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).…”

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confidence: 99%

“…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).…”

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Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Bourguignon

Wong

Shiina

2016

Journal of Biological Chemistry

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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...

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Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Bourguignon

Wong

Shiina

2016

Journal of Biological Chemistry

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miR‐372 and miR‐373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways

Wang

et al. 2018

Molecular Oncology

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miR‐372/373, a cluster of stem cell‐specific microRNAs transactivated by the Wnt pathway, has been reported to be dysregulated in various cancers, particularly colorectal cancer (CRC); however, the unique role of these microRNAs in cancer remains to be discovered. In the present study, we characterized the upregulation in expression of miR‐372/373 in CRC tissues from The Cancer Genome Atlas data, and then showed that overexpression of miR‐372/373 enhanced the stemness of CRC cells by enriching the CD26/CD24‐positive cell population and promoting self‐renewal, chemotherapy resistance and the invasive potential of CRC cells. To clarify the mechanism underlying microRNA‐induced stemness, we profiled 45 cell signaling pathways in CRC cells overexpressing miR‐372/373 and found that stemness‐related pathways, such as Nanog and Hedgehog, were upregulated. Instead, differentiation‐related pathways, such as NFκB, MAPK/Erk and VDR, were markedly repressed by miR‐372/373. Numerous new targets of miR‐372/373 were identified, including SPOP, VDR and SETD7, all of which are factors important for cell differentiation. Furthermore, in contrast to the increase in miR‐372/373 expression in CRC tissues, the expression levels of SPOP and VDR mRNA were significantly downregulated in these tissues, indicative of the poor differentiation status of CRC. Taken together, our findings suggest that miR‐372/373 enhance CRC cell stemness by repressing the expression of differentiation genes. These results provide new insights for understanding the function and mechanisms of stem cell‐specific microRNAs in the development of metastasis and drug resistance in CRC.

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Cancer Stem Cells – Basic Biological Properties and Experimental Approaches

Hatina

Fernandes

Hoffmann

et al. 2013

Encyclopedia of Life Sciences

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Cancer stem cells (CSCs) are defined as a self‐renewing and self‐protecting subpopulation of tumour cells that can differentiate into all other tumour cell types found within a tumour. They can be prospectively identified and purified, either on the basis of specific cell surface marker expression, or by virtue of their biological properties; their self‐protection has been harnessed to develop several purification strategies, for example, side population or Aldefluor assays. Other prominent biological properties of CSCs include their exclusive clonogenicity and tumourigenicity. Many of these basic biological characteristics are shared between normal and CSCs, as are multiple signalling pathways regulating self‐renewal and differentiation. Unlike normal stem cells, CSCs often seem to be distinctly less stable, dynamically modulating their stemness and differentiation according to various environmental signals and/or genetic and epigenetic changes accumulated during the carcinogenic process. This plasticity of CSCs might underlie the prominent biological characteristics of malignant tumours, especially their propensity to metastasise. Key Concepts: Stem cells are long‐lived and protect their genome. Existence of long‐lived, undifferentiated and self‐protecting cells could be indirectly inferred in tumours. Cancer stem cells express specific cell surface markers and are amenable to differential staining procedures. Cancer stem cells frequently exploit similar signalling pathways as embryonic stem cells and normal adult stem cells. Hypoxia activates a multifaceted stem cell programme in tumours. Cancer stem cell phenotype can be unstable, with repeated or even ongoing differentiation and dedifferentiation.

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Hyaluronan-CD44v3 Interaction with Oct4-Sox2-Nanog Promotes miR-302 Expression Leading to Self-renewal, Clonal Formation, and Cisplatin Resistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Cited by 257 publications

References 71 publications

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

miR‐372 and miR‐373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways

Cancer Stem Cells – Basic Biological Properties and Experimental Approaches

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