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Article: Matrix Hyaluronan-CD44 Interaction Activates MicroRNA and LncRNA Signaling Associated With Chemoresistance, Invasion, and Tumor Progression.

Bourguignon, Lilly Y W

2019 Volume 9, Page(s) 492

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2019-06-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.00492
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression.

Bourguignon, Lilly Y W

International journal of molecular sciences

2016 Volume 17, Issue 4, Page(s) 517

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 ...

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.
MeSH term(s)	Animals ; Drug Resistance, Neoplasm ; Extracellular Matrix/metabolism ; Extracellular Matrix/pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Hyaluronan Receptors/metabolism ; Hyaluronic Acid/metabolism ; MicroRNAs/genetics ; Neoplasm Invasiveness/genetics ; Neoplasm Invasiveness/pathology ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Up-Regulation
Chemical Substances	Hyaluronan Receptors ; MicroRNAs ; Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2016-04-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms17040517
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Article ; Online: Matrix hyaluronan-activated CD44 signaling promotes keratinocyte activities and improves abnormal epidermal functions.

Bourguignon, Lilly Y W

The American journal of pathology

2014 Volume 184, Issue 7, Page(s) 1912–1919

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Animals ; Calcium Signaling ; Cytoskeleton/metabolism ; Epidermal Cells ; Epidermis/physiopathology ; Humans ; Hyaluronan Receptors/metabolism ; Hyaluronic Acid/metabolism ; Keratinocytes/cytology ; Mice, Knockout ; Signal Transduction ; Skin Aging ; rho-Associated Kinases ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Hyaluronan Receptors ; Hyaluronic Acid (9004-61-9) ; rho-Associated Kinases (EC 2.7.11.1) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2014-05-09
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2014.03.010
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Article ; Online: Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression

Lilly Y. W. Bourguignon

International Journal of Molecular Sciences, Vol 17, Iss 4, p

2016 Volume 517

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	hyaluronan (HA) ; CD44 ; microRNA (miRNA) ; cancer stem cells (CSCs) ; signaling ; chemoresistance ; tumor progression ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2016-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Hyaluronan-CD44 interaction promotes HPV 16 E6 oncogene-mediated oropharyngeal cell carcinoma survival and chemoresistance.

Bourguignon, Lilly Y W / Earle, Christine / Shiina, Marisa

Matrix biology : journal of the International Society for Matrix Biology

2018 Volume 78-79, Page(s) 180–200

Abstract: Head and neck squamous cell carcinoma (HNSCC) is a malignancy that often involves the oral cavity, pharynx, larynx, or paranasal sinuses. There is a compelling evidence of the human papilloma virus including HPV16 E6 oncogene drives cell transformation ... ...

Abstract	Head and neck squamous cell carcinoma (HNSCC) is a malignancy that often involves the oral cavity, pharynx, larynx, or paranasal sinuses. There is a compelling evidence of the human papilloma virus including HPV16 E6 oncogene drives cell transformation and oncogenic processes of HPV positive (HVP+) HNSCC [in particular, Oropharyngeal Squamous Cell Carcinoma (OPSCC)]. In this study, we determined that human OPSCC-derived, HPV16 E6+ cells (UMSCC-104 and UMSCC-47 cell lines) express CD44 and a regulatory transcription factor, c-Jun. Importantly, interaction between matrix hyaluronan (HA) and CD44 (an HA receptor) promotes c-Jun phosphorylation followed by phospho-c-Jun nuclear translocation and co-localization with HPV16 E6 in the nucleus of both UMSCC-104 and UMSCC-47 cells. Further analyses revealed that HPV16 E6 expression is regulated by an upstream promoter containing AP1/c-Jun binding site(s), and chromatin immunoprecipitation (ChIP) assays demonstrated that stimulation of HPV16 E6 expression by HA-CD44 interaction is phospho-c-Jun dependent in these HPV16+ UMSCC-104 and UMSCC-47 cells. This process results in an upregulation of survival proteins, inhibitors of the apoptosis family of proteins (IAPs) and chemoresistance in these HPV16+ cells. Treatment of UMSCC-104 or UMSCC-47 cells with c-Jun-specific or HPV16 E6-specific small interfering RNAs effectively blocks HA/CD44-mediated c-Jun signaling and abrogates HPV16 E6 expression as well as causes downregulation of survival proteins (cIAP-1 and cIAP-2) expression and enhancement of chemosensitivity. Together, these findings suggest that the HA/CD44-induced c-Jun signaling plays a pivotal role in HPV16 E6 upregulation leading to survival protein (cIAP-1/cIAP-2) production and chemoresistance in HPV16+ UMSCC-104 and UMSCC-47 cells. Most importantly, using a mouse xenograft model, we have observed that Cisplatin chemotherapy combined with the suppression of CD44, c-Jun and HPV16 E6 (by treating both UMSCC-104 cells and UMSCC-47 cells with CD44shRNA or c-Jun shRNA or HPV16 E6 shRNA) appears to be more effective in tumor size reduction than chemotherapy alone. Thus, these newly-discovered HA/CD44-c-Jun/HPV16E6 signaling pathways may provide new drug targets for overcoming cisplatin chemoresistance in HPV16E6-positive OPSCC cells.
MeSH term(s)	Animals ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/virology ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cell Survival/drug effects ; Cisplatin/administration & dosage ; Cisplatin/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Human papillomavirus 16/metabolism ; Human papillomavirus 16/pathogenicity ; Humans ; Hyaluronan Receptors/antagonists & inhibitors ; Hyaluronan Receptors/genetics ; Hyaluronan Receptors/metabolism ; Hyaluronic Acid/metabolism ; Mice ; Oncogene Proteins, Viral/antagonists & inhibitors ; Oncogene Proteins, Viral/genetics ; Oncogene Proteins, Viral/metabolism ; Oropharyngeal Neoplasms/drug therapy ; Oropharyngeal Neoplasms/metabolism ; Oropharyngeal Neoplasms/virology ; Papillomavirus Infections/drug therapy ; Papillomavirus Infections/metabolism ; Phosphorylation/drug effects ; Protein Transport ; Proto-Oncogene Proteins c-jun/antagonists & inhibitors ; Proto-Oncogene Proteins c-jun/genetics ; Proto-Oncogene Proteins c-jun/metabolism ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/pharmacology ; Repressor Proteins/antagonists & inhibitors ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	CD44 protein, human ; E6 protein, Human papillomavirus type 16 ; Hyaluronan Receptors ; JUN protein, human ; Oncogene Proteins, Viral ; Proto-Oncogene Proteins c-jun ; RNA, Small Interfering ; Repressor Proteins ; Hyaluronic Acid (9004-61-9) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2018-08-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2018.07.008
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Article: Selective Activation of Cancer Stem Cells by Size-Specific Hyaluronan in Head and Neck Cancer.

Shiina, Marisa / Bourguignon, Lilly Y W

International journal of cell biology

2015 Volume 2015, Page(s) 989070

Abstract: 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 different sizes of hyaluronan (HA) (e.g., 5 kDa, 20 ...

Abstract	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 different sizes of hyaluronan (HA) (e.g., 5 kDa, 20 kDa, 200 kDa, or 700 kDa-HA-sizes) play a role in regulating these CSCs. First, we observed that 200 kDa-HA (but not other sizes of HA) preferentially induces certain stem cell marker expression resulting in self-renewal and clonal formation of these cells. Further analyses indicate that 200 kDa-HA selectively stimulates the expression of a panel of microRNAs (most noticeably miR-10b) in these CSCs. Survival protein (cIAP-1) expression was also stimulated by 200 kDa-HA in these CSCs leading to cisplatin resistance. Furthermore, our results indicate that the anti-miR-10 inhibitor not only decreases survival protein expression, but also increases chemosensitivity of the 200 kDa-HA-treated CSCs. These findings strongly support the contention that 200 kDa-HA plays a pivotal role in miR-10 production leading to survival protein upregulation and chemoresistance in CSCs. Together, our findings suggest that selective activation of oncogenic signaling by certain sizes of HA (e.g., 200 kDa-HA) may be instrumental in the formation of CSC functions leading to tumor cell survival and chemoresistance in head and neck cancer progression.
Language	English
Publishing date	2015-09-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2536742-0
ISSN	1687-8884 ; 1687-8876
ISSN (online)	1687-8884
ISSN	1687-8876
DOI	10.1155/2015/989070
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Article: Selective Hyaluronan-CD44 Signaling Promotes miRNA-21 Expression and Interacts with Vitamin D Function during Cutaneous Squamous Cell Carcinomas Progression Following UV Irradiation.

Bourguignon, Lilly Y W / Bikle, Daniel

Frontiers in immunology

2015 Volume 6, Page(s) 224

Abstract: 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 squamous cell carcinomas ( ... ...

Abstract	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 squamous cell carcinomas (SCC) overexpress a variety of CD44 variant isoforms (CD44v), with different CD44v isoforms appear to confer malignant SCC properties. UVR also stimulates HA degradation in epidermal keratinocytes. Both large HA polymers and their UVR-induced catabolic products (small HA) selectively activate CD44-mediated cellular signaling in normal keratinocytes and SCC cells, with all of the downstream processes being mediated by RhoGTPases (e.g., Rac1 and Rho). Importantly, we found that the hormonally active form of vitamin D 1,25(OH)2D3 not only prevents the UVR-induced small HA activation of abnormal keratinocyte behavior and SCC progression, but also enhances large HA stimulation of normal keratinocyte activities and epidermal function(s). The aim of this hypothesis and theory article is to question whether matrix HA and its UVR-induced catabolic products (e.g., large and small HA) can selectively activate CD44-mediated cellular signaling such as GTPase (Rac and RhA) activation. We suggested that large HA-CD44 interaction promotes Rac-signaling and normal keratinocyte differentiation (lipid synthesis), DNA repair, and keratinocyte survival function. Conversely, small HA-CD44 interaction stimulates RhoA activation, NFκB/Stat-3 signaling, and miR-21 production, resulting in inflammation and proliferation as well as SCC progression. We also question whether vitamin D treatment displays any effect on small HA-CD44v-mediated RhoA signaling, inflammation, and SCC progression, as well as large HA-CD44-mediated differentiation, DNA repair, keratinocyte survival, and normal keratinocyte function. In addition, we discussed that the topical application of signaling perturbation agents (e.g., Y27623, a ROK inhibitor) may be used to treat certain skin diseases displaying upregulation of keratinocyte proliferation such as psoriasis and actinic keratoses in order to correct the imbalance between Rac and RhoA signaling during various UV irradiation-induced skin diseases in patients. Finally, we proposed that matrix HA/CD44-signaling strategies and matrix HA (HAS vs. HAL or HAS → HAL)-based therapeutic approaches (together with vitamin D) may be used for the treatment of patients suffering a number of UV irradiation-induced skin diseases (e.g., inflammation, skin cancer, and chronic non-healing wounds).
Language	English
Publishing date	2015-05-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2015.00224
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Article ; Online: Hyaluronan-CD44 interaction promotes microRNA signaling and RhoGTPase activation leading to tumor progression.

Bourguignon, Lilly Y W

Small GTPases

2012 Volume 3, Issue 1, Page(s) 53–59

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Carcinoma, Squamous Cell/metabolism ; Drug Resistance, Neoplasm ; Head and Neck Neoplasms/metabolism ; Homeodomain Proteins/metabolism ; Humans ; Hyaluronan Receptors/metabolism ; Hyaluronic Acid/metabolism ; MicroRNAs/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction
Chemical Substances	Homeodomain Proteins ; Hyaluronan Receptors ; MicroRNAs ; STAT3 Transcription Factor ; Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2012-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
ZDB-ID	2682247-7
ISSN	2154-1256 ; 2154-1248
ISSN (online)	2154-1256
ISSN	2154-1248
DOI	10.4161/sgtp.19110
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Article ; Online: Activation of Matrix Hyaluronan-Mediated CD44 Signaling, Epigenetic Regulation and Chemoresistance in Head and Neck Cancer Stem Cells.

Bourguignon, Lilly Y W / Earle, Christine / Shiina, Marisa

International journal of molecular sciences

2017 Volume 18, Issue 9

Abstract: 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, ...

Abstract	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 CD44v3
Language	English
Publishing date	2017-08-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms18091849
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Article ; Online: Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells.

Chen, Liqun / Bourguignon, Lilly Y W

Molecular cancer

2014 Volume 13, Page(s) 52

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; Drug Resistance, Neoplasm/physiology ; Female ; Fluorescent Antibody Technique ; Gene Expression Regulation, Neoplastic/physiology ; Humans ; Hyaluronan Receptors/metabolism ; Hyaluronic Acid/metabolism ; Immunoblotting ; MicroRNAs/biosynthesis ; MicroRNAs/genetics ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-jun/metabolism ; Signal Transduction/physiology ; Transfection
Chemical Substances	CD44 protein, human ; Hyaluronan Receptors ; MIRN21 microRNA, human ; MicroRNAs ; Proto-Oncogene Proteins c-bcl-2 ; Proto-Oncogene Proteins c-jun ; Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2014-03-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1476-4598
ISSN (online)	1476-4598
DOI	10.1186/1476-4598-13-52
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