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For: Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, Konishi I. Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. J Transl Med 2003;83:861-70. [PMID: 12808121 DOI: 10.1097/01.lab.0000073128.16098.31] [Citation(s) in RCA: 180] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open

For:	Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, Konishi I. Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. J Transl Med 2003;83:861-70. [PMID: 12808121 DOI: 10.1097/01.lab.0000073128.16098.31] [Citation(s) in RCA: 180] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open

Number

Cited by Other Article(s)

Smout JL, Bain MM, McLaughlin M, Elmer KR. Common lizard primary oviduct cell culture: A model system for the genetic and cellular basis of oviparity and viviparity. Exp Cell Res 2024;442:114196. [PMID: 39117090 DOI: 10.1016/j.yexcr.2024.114196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/16/2024] [Accepted: 08/02/2024] [Indexed: 08/10/2024]

Mikhael S, Kurdi A, Khoueiry-Zgheib N, Tahtouh R, Nasr R, Hilal G. Evaluating synergistic effects of metformin and simvastatin on ovarian cancer cells. PLoS One 2024;19:e0298127. [PMID: 38489280 PMCID: PMC10942021 DOI: 10.1371/journal.pone.0298127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 01/19/2024] [Indexed: 03/17/2024] Open

Abstract

BACKGROUND

Ovarian Cancer (OC) stands as the most lethal gynecological malignancy, presenting an urgent clinical challenge in the quest to improve response rates. One approach to address this challenge is through drug repurposing, exemplified by the investigation of metabolic-modulating drugs such as Metformin (MTF) and Simvastatin (SIM). This study aims to explore the molecular mechanisms contributing to the potential synergistic anti-cancer effects between MTF and SIM on ovarian cancer cells.

METHODS

We assessed the effects of the combination on the proliferation and viability of two cell lines OVCAR-3 and SKOV-3. IC50 concentrations of MTF and SIM were determined using a proliferation assay, followed by subtoxic concentrations to explore the potential synergistic effects on the viability of both cell lines. Transcriptomic analysis was conducted on OVCAR-3 treated cells, and the findings were validated by assessing the expression levels of differentially expressed genes (DEGs) through real-time PCR in both cell lines SK-OV-3 and OVCAR-3.

RESULTS

Cytotoxicity analysis guided the selection of treatment concentrations as such MTF 10 mM and SIM 5 μM. The combined treatment of MTF and SIM demonstrated a synergistic inhibition of proliferation and viability in both cell lines. In OVCAR-3, exclusive identification of 507 DEGs was seen in the combination arm. Upregulation of FOXO3, RhoA, and TNFα, along with downregulation of PIK3R1, SKP2, and ATP6V1D levels, was observed in OVCAR-3 treated cells. Real-time PCR validation confirmed the consistency of expression levels for the mentioned DEGs.

CONCLUSION

Our data strongly supports the presence of synergy between MTF and SIM in OC cells. The combination's effect is associated with the dysregulation of genes in the key regulators AMPK and mTOR alongside other interconnected pathways.

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Hunt AL, Bateman NW, Barakat W, Makohon-Moore SC, Abulez T, Driscoll JA, Schaaf JP, Hood BL, Conrads KA, Zhou M, Calvert V, Pierobon M, Loffredo J, Wilson KN, Litzi TJ, Teng PN, Oliver J, Mitchell D, Gist G, Rojas C, Blanton B, Darcy KM, Rao UNM, Petricoin EF, Phippen NT, Maxwell GL, Conrads TP. Mapping three-dimensional intratumor proteomic heterogeneity in uterine serous carcinoma by multiregion microsampling. Clin Proteomics 2024;21:4. [PMID: 38254014 PMCID: PMC10804562 DOI: 10.1186/s12014-024-09451-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 01/14/2024] [Indexed: 01/24/2024] Open

Abstract

BACKGROUND

Although uterine serous carcinoma (USC) represents a small proportion of all uterine cancer cases, patients with this aggressive subtype typically have high rates of chemotherapy resistance and disease recurrence that collectively result in a disproportionately high death rate. The goal of this study was to provide a deeper view of the tumor microenvironment of this poorly characterized uterine cancer variant through multi-region microsampling and quantitative proteomics.

METHODS

Tumor epithelium, tumor-involved stroma, and whole "bulk" tissue were harvested by laser microdissection (LMD) from spatially resolved levels from nine USC patient tumor specimens and underwent proteomic analysis by mass spectrometry and reverse phase protein arrays, as well as transcriptomic analysis by RNA-sequencing for one patient's tumor.

RESULTS

LMD enriched cell subpopulations demonstrated varying degrees of relatedness, indicating substantial intratumor heterogeneity emphasizing the necessity for enrichment of cellular subpopulations prior to molecular analysis. Known prognostic biomarkers were quantified with stable levels in both LMD enriched tumor and stroma, which were shown to be highly variable in bulk tissue. These USC data were further used in a comparative analysis with a data generated from another serous gynecologic malignancy, high grade serous ovarian carcinoma, and have been added to our publicly available data analysis tool, the Heterogeneity Analysis Portal ( https://lmdomics.org/ ).

CONCLUSIONS

Here we identified extensive three-dimensional heterogeneity within the USC tumor microenvironment, with disease-relevant biomarkers present in both the tumor and the stroma. These data underscore the critical need for upfront enrichment of cellular subpopulations from tissue specimens for spatial proteogenomic analysis.

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Affiliation(s)

Allison L Hunt Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Suite 375, Annandale, VA, 22042, USA Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
Nicholas W Bateman Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA Department of Surgery, The John P. Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
Waleed Barakat Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Sasha C Makohon-Moore Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Tamara Abulez Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Jordan A Driscoll Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Joshua P Schaaf Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Brian L Hood Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Kelly A Conrads Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Ming Zhou Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Suite 375, Annandale, VA, 22042, USA Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
Valerie Calvert Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
Mariaelena Pierobon Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
Jeremy Loffredo Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Katlin N Wilson Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Tracy J Litzi Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Pang-Ning Teng Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Julie Oliver Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Dave Mitchell Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Glenn Gist Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Christine Rojas Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
Brian Blanton Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Kathleen M Darcy Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA Department of Surgery, The John P. Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
Uma N M Rao Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
Emanuel F Petricoin Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
Neil T Phippen Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA Department of Surgery, The John P. Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
G Larry Maxwell Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Suite 375, Annandale, VA, 22042, USA Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA Department of Surgery, The John P. Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
Thomas P Conrads Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Suite 375, Annandale, VA, 22042, USA. Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. Department of Surgery, The John P. Murtha Cancer Center Research Program, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.

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Lee YCG, Chou FN, Tung SY, Chou HC, Ko TL, Fann YC, Juan SH. Tumoricidal Activity of Simvastatin in Synergy with RhoA Inactivation in Antimigration of Clear Cell Renal Cell Carcinoma Cells. Int J Mol Sci 2023;24:ijms24119738. [PMID: 37298689 DOI: 10.3390/ijms24119738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/30/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open

Banushi B, Joseph SR, Lum B, Lee JJ, Simpson F. Endocytosis in cancer and cancer therapy. Nat Rev Cancer 2023:10.1038/s41568-023-00574-6. [PMID: 37217781 DOI: 10.1038/s41568-023-00574-6] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/11/2023] [Indexed: 05/24/2023]

Morishita J, Nurse P. Identification of a small RhoA GTPase inhibitor effective in fission yeast and human cells. Open Biol 2023;13:220185. [PMID: 36854376 PMCID: PMC9974304 DOI: 10.1098/rsob.220185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open

Gugnoni M, Manzotti G, Vitale E, Sauta E, Torricelli F, Reggiani F, Pistoni M, Piana S, Ciarrocchi A. OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer. J Exp Clin Cancer Res 2022;41:108. [PMID: 35337349 PMCID: PMC8957195 DOI: 10.1186/s13046-022-02316-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 03/08/2022] [Indexed: 11/10/2022] Open

Abstract

Background

Anaplastic Thyroid Cancer (ATC) is an undifferentiated and aggressive tumor that often originates from well-Differentiated Thyroid Carcinoma (DTC) through a trans-differentiation process. Epithelial-to-Mesenchymal Transition (EMT) is recognized as one of the major players of this process. OVOL2 is a transcription factor (TF) that promotes epithelial differentiation and restrains EMT during embryonic development. OVOL2 loss in some types of cancers is linked to aggressiveness and poor prognosis. Here, we aim to clarify the unexplored role of OVOL2 in ATC.

Methods

Gene expression analysis in thyroid cancer patients and cell lines showed that OVOL2 is mainly associated with epithelial features and its expression is deeply impaired in ATC. To assess OVOL2 function, we established an OVOL2-overexpression model in ATC cell lines and evaluated its effects by analyzing gene expression, proliferation, invasion and migration abilities, cell cycle, specific protein localization through immunofluorescence staining. RNA-seq profiling showed that OVOL2 controls a complex network of genes converging on cell cycle and mitosis regulation and Chromatin Immunoprecipitation identified new OVOL2 target genes.

Results

Coherently with its reported function, OVOL2 re-expression restrained EMT and aggressiveness in ATC cells. Unexpectedly, we observed that it caused G2/M block, a consequent reduction in cell proliferation and an increase in cell death. This phenotype was associated to generalized abnormalities in the mitotic spindle structure and cytoskeletal organization. By RNA-seq experiments, we showed that many pathways related to cytoskeleton and migration, cell cycle and mitosis are profoundly affected by OVOL2 expression, in particular the RHO-GTPase pathway resulted as the most interesting. We demonstrated that RHO GTPase pathway is the central hub of OVOL2-mediated program in ATC and that OVOL2 transcriptionally inhibits RhoU and RhoJ. Silencing of RhoU recapitulated the OVOL2-driven phenotype pointing to this protein as a crucial target of OVOL2 in ATC.

Conclusions

Collectively, these data describe the role of OVOL2 in ATC and uncover a novel function of this TF in inhibiting the RHO GTPase pathway interlacing its effects on EMT, cytoskeleton dynamics and mitosis.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13046-022-02316-2.

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Konishi I, Abiko K, Hayashi T, Yamanoi K, Murakami R, Yamaguchi K, Hamanishi J, Baba T, Matsumura N, Mandai M. Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics. J Gynecol Oncol 2022;33:e83. [PMID: 36032027 PMCID: PMC9428305 DOI: 10.3802/jgo.2022.33.e83] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 12/02/2022] Open

Bakherad H, Ghasemi F, Hosseindokht M, Zare H. Nanobodies; new molecular instruments with special specifications for targeting, diagnosis and treatment of triple-negative breast cancer. Cancer Cell Int 2022;22:245. [PMID: 35933373 PMCID: PMC9357333 DOI: 10.1186/s12935-022-02665-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 07/27/2022] [Indexed: 11/10/2022] Open

Huang Z, Zhang Z, Zhou C, Liu L, Huang C. Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities. MedComm (Beijing) 2022;3:e144. [PMID: 35601657 PMCID: PMC9115588 DOI: 10.1002/mco2.144] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/05/2023] Open

The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer. Clin Sci (Lond) 2022;136:197-222. [PMID: 35119068 PMCID: PMC8819670 DOI: 10.1042/cs20201474] [Citation(s) in RCA: 156] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/05/2022] [Accepted: 01/18/2022] [Indexed: 02/07/2023]

Malik JA, Ahmed S, Jan B, Bender O, Al Hagbani T, Alqarni A, Anwar S. Drugs repurposed: An advanced step towards the treatment of breast cancer and associated challenges. Biomed Pharmacother 2021;145:112375. [PMID: 34863612 DOI: 10.1016/j.biopha.2021.112375] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/15/2021] [Accepted: 10/25/2021] [Indexed: 02/09/2023] Open

Riazalhosseini B, Mohamed R, Devi Apalasamy Y, Mohamed Z. Association of deleted in liver cancer-1 gene polymorphism with increased risk of chronicity of disease among Malaysian patients with hepatitis B infection. Pharmacogenet Genomics 2021;31:185-190. [PMID: 34320605 DOI: 10.1097/fpc.0000000000000439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]

Yang SH, Liu W, Peng J, Xu YJ, Liu YF, Li Y, Peng MY, Ou-Yang Z, Chen C, Liu EY. High Expression of RhoBTB3 Predicts Favorable Chemothrapy Outcomes in non-M3 Acute Myeloid Leukemia. J Cancer 2021;12:4229-4239. [PMID: 34093823 PMCID: PMC8176412 DOI: 10.7150/jca.50472] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 04/25/2021] [Indexed: 11/05/2022] Open

Abstract

Background: The expression patterns and prognostic significance of the Rho family GTPases in acute myeloid leukemia have not been systematically studied yet.

Methods: In our study, we analyzed the expression patterns of 21 Rho family GTPases gene members in AML patients based on GEPIA database. 10 gene members with significant differential expression in AML tissue and healthy tissue were selected for subsequent research. Survival curve analysis in TCGA and GEO dataset preliminary showed that RhoBTB3 is related with the prognosis of non-M3 AML patients. The differential expression of RhoBTB3 on AML bone marrow and normal bone marrow was verified by RT-qPCR. We performed Kaplan-Meier survival analysis and Multivariate Cox analysis to assess the prognostic value of RhoBTB3 in non-M3 AML patients with different treatment regimens. Gene functional enrichment analysis of RhoBTB3 was performed using GO, KEGG and PPI network.

Results: The AML patients from TCGA database were partitioned into 2 groups based on different treatment regimens: chemotherapy group and allo-HSCT group. In chemotherapy group, patients with higher expression level of RhoBTB3 showed relatively longer OS and EFS, multivariate Cox analysis revealed high RhoBTB3 mRNA expression as an independent favorable prognostic factor. However, in allo-HSCT group, no significant difference of OS and EFS were found between RhoBTB3 high and low subgroups. Meanwhile, allo-HSCT could circumvent the unfavorable prognosis that was associated with downregulation of RhoBTB3. Functional enrichment analysis showed the association of RhoBTB3 expression with several fundamental physiological components and pathways, including extracellular matrix components, extracellular structure organization, and cytokine-cytokine receptor interaction.

Conclusions: Our study identified RhoBTB3 as a prognostic marker and may aid in the selection of the appropriate treatment options between chemotherapy and allo-HCST in non-M3 AML patients. Further researches are necessary to clarify the involvement of RhoBTB3 in the pathogenesis of AML.

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Keller L, Tardy C, Ligat L, Gilhodes J, Filleron T, Bery N, Rochaix P, Aquilina A, Bdioui S, Roux T, Trinquet E, Favre G, Olichon A. Nanobody-Based Quantification of GTP-Bound RHO Conformation Reveals RHOA and RHOC Activation Independent from Their Total Expression in Breast Cancer. Anal Chem 2021;93:6104-6111. [PMID: 33825439 DOI: 10.1021/acs.analchem.0c05137] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]

Effects of Amyloid Precursor Protein Overexpression on NF-κB, Rho-GTPase and Pro-Apoptosis Bcl-2 Pathways in Neuronal Cells. Rep Biochem Mol Biol 2021;9:417-425. [PMID: 33969135 DOI: 10.52547/rbmb.9.4.417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]

Limzerwala JF, Jeganathan KB, Kloeber JA, Davies BA, Zhang C, Sturmlechner I, Zhong J, Fierro Velasco R, Fields AP, Yuan Y, Baker DJ, Zhou D, Li H, Katzmann DJ, van Deursen JM. FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling to drive cancer. NATURE CANCER 2020;1:1010-1024. [PMID: 34841254 PMCID: PMC8623810 DOI: 10.1038/s43018-020-00116-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 08/17/2020] [Indexed: 01/28/2023]

AL-Eitan LN, ababa’h DM, Aman HA. The Associations of Common Genetic Susceptibility Variants with Breast Cancer in Jordanian Arabs: A Case-Control Study. Asian Pac J Cancer Prev 2020;21:3045-3054. [PMID: 33112566 PMCID: PMC7798142 DOI: 10.31557/apjcp.2020.21.10.3045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open

Chen X, Yuan XN, Zhang Z, Gong PJ, Yin WN, Jiang Q, Xu J, Xu XL, Gao Y, Chen WL, Chen FF, Tian YH, Wei L, Zhang JW. Betulinic acid inhibits cell proliferation and migration in gastric cancer by targeting the NF-κB/VASP pathway. Eur J Pharmacol 2020;889:173493. [PMID: 32860808 DOI: 10.1016/j.ejphar.2020.173493] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 08/11/2020] [Accepted: 08/19/2020] [Indexed: 01/06/2023]

Affiliation(s)

Xiang Chen Department of Breast and Thyroid Surgery, Zhongnan Hospital, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, 430071, Hubei, China; Department of Pathology, Central Theater Command General Hospital, People's Liberation Army of China, Wuhan, 430070, Hubei, China
Xiao-Ning Yuan Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
Zun Zhang Department of Breast and Thyroid Surgery, Renmin Hospital, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, 430071, Hubei, China
Peng-Ju Gong Department of Breast and Thyroid Surgery, Zhongnan Hospital, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, 430071, Hubei, China
Wei-Nan Yin Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
Qi Jiang Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
Jingjing Xu Department of Breast and Thyroid Surgery, Zhongnan Hospital, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, 430071, Hubei, China
Xiao-Long Xu Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
Yang Gao Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
Wen-Li Chen Division of Nephrology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, Hubei, China
Fang-Fang Chen Department of Breast and Thyroid Surgery, Zhongnan Hospital, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, 430071, Hubei, China
Yi-Hao Tian Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
Lei Wei Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
Jing-Wei Zhang Department of Breast and Thyroid Surgery, Zhongnan Hospital, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan University, Wuhan, 430071, Hubei, China.

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Leukemia-Associated Rho Guanine Nucleotide Exchange Factor and Ras Homolog Family Member C Play a Role in Glioblastoma Cell Invasion and Resistance. THE AMERICAN JOURNAL OF PATHOLOGY 2020;190:2165-2176. [PMID: 32693062 DOI: 10.1016/j.ajpath.2020.07.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/16/2020] [Accepted: 07/07/2020] [Indexed: 11/23/2022]

Levy A, Alhazzani K, Dondapati P, Alaseem A, Cheema K, Thallapureddy K, Kaur P, Alobid S, Rathinavelu A. Focal Adhesion Kinase in Ovarian Cancer: A Potential Therapeutic Target for Platinum and Taxane-Resistant Tumors. Curr Cancer Drug Targets 2020;19:179-188. [PMID: 29984656 DOI: 10.2174/1568009618666180706165222] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 04/30/2018] [Accepted: 05/31/2018] [Indexed: 12/12/2022]

Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare. Cancers (Basel) 2020;12:cancers12051292. [PMID: 32443784 PMCID: PMC7281750 DOI: 10.3390/cancers12051292] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/24/2022] Open

Tanaka K, Matsumoto Y, Ishikawa H, Fukumitsu N, Numajiri H, Murofushi K, Oshiro Y, Okumura T, Satoh T, Sakurai H. Impact of RhoA overexpression on clinical outcomes in cervical squamous cell carcinoma treated with concurrent chemoradiotherapy. JOURNAL OF RADIATION RESEARCH 2020;61:221-230. [PMID: 31976530 PMCID: PMC7246076 DOI: 10.1093/jrr/rrz093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 11/05/2019] [Indexed: 05/04/2023]

Cen B, Lang JD, Du Y, Wei J, Xiong Y, Bradley N, Wang D, DuBois RN. Prostaglandin E₂ Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression. Gastroenterology 2020;158:971-984.e10. [PMID: 31734182 PMCID: PMC7062589 DOI: 10.1053/j.gastro.2019.11.013] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 09/20/2019] [Accepted: 11/01/2019] [Indexed: 12/15/2022]

Abstract

BACKGROUND & AIMS

Prostaglandin E₂ (PGE₂) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE₂ on colorectal cancer (CRC) development.

METHODS

We incubated LS174T colorectal cancer cells with PGE₂ or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative polymerase chain reaction, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NOD-scidIL-2Rg^-/- mice were given injections of LS174T cells, and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes.

RESULTS

We identified miRNA 675-5p (miR675-5p) as the miRNA most highly up-regulated by incubation of colorectal cancer cells with PGE₂. PGE₂ increased expression of miR675-5p by activating expression of Myc, via activation of protein kinase B, also known as (AKT), nuclear factor κB, and β-catenin. PGE₂ increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE₂ formed more liver and lung metastases in mice than control LS174T cells. We identified a 3' untranslated region in the TP53 messenger RNA that bound miR675-5p; binding resulted in loss of the p53 protein. Expression of miR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC.

CONCLUSIONS

We found that treatment of mice with PGE₂ increased CRC cells invasive activity and ability to form liver and lung metastases. PGE₂ down-regulates expression of p53 by increasing expression of miR675-5p, which binds to and prevents translation of TP53 messenger RNA. These findings provide insight into the mechanisms by which PGE₂ promotes tumor development and progression. Strategies to target PGE₂ might be developed for treatment of CRC.

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Reduced RhoA expression enhances breast cancer metastasis with a concomitant increase in CCR5 and CXCR4 chemokines signaling. Sci Rep 2019;9:16351. [PMID: 31705019 PMCID: PMC6841971 DOI: 10.1038/s41598-019-52746-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/22/2019] [Indexed: 12/31/2022] Open

Wang LL, Zong ZH, Liu Y, Guan X, Chen S, Zhao Y. CircRhoC promotes tumorigenicity and progression in ovarian cancer by functioning as a miR-302e sponge to positively regulate VEGFA. J Cell Mol Med 2019;23:8472-8481. [PMID: 31639291 PMCID: PMC6850961 DOI: 10.1111/jcmm.14736] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 08/30/2019] [Accepted: 09/18/2019] [Indexed: 01/19/2023] Open

Affiliation(s)

Li-Li Wang Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institute in Guangdong Province, Guangzhou, China
Zhi-Hong Zong Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institute in Guangdong Province, Guangzhou, China
Yao Liu Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, China
Xue Guan Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, China
Shuo Chen Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institute in Guangdong Province, Guangzhou, China
Yang Zhao Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institute in Guangdong Province, Guangzhou, China

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Joseph J, Radulovich N, Wang T, Raghavan V, Zhu CQ, Tsao MS. Rho guanine nucleotide exchange factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma. Oncogene 2019;39:308-321. [DOI: 10.1038/s41388-019-0985-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 06/10/2019] [Accepted: 06/15/2019] [Indexed: 12/18/2022]

Arisanty D, Harahap WA, Khambri D, Rustam R, Aliska G, Achyar A, Menra JP. The Comparison of RhoC and PI3K Gene Expression on the Breast Cancer Tissue and Benign Tumour Tissue. Open Access Maced J Med Sci 2019;7:1911-1916. [PMID: 31406528 PMCID: PMC6684428 DOI: 10.3889/oamjms.2019.543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/07/2019] [Accepted: 06/08/2019] [Indexed: 01/07/2023] Open

Chang CC, Huang KH, Hsu SP, Lee YCG, Sue YM, Juan SH. Simvastatin reduces the carcinogenic effect of 3-methylcholanthrene in renal epithelial cells through histone deacetylase 1 inhibition and RhoA reactivation. Sci Rep 2019;9:4606. [PMID: 30872677 PMCID: PMC6418087 DOI: 10.1038/s41598-019-40757-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 09/21/2018] [Indexed: 12/24/2022] Open

Egiz M, Usui T, Ishibashi M, Zhang X, Shigeta S, Toyoshima M, Kitatani K, Yaegashi N. La-Related Protein 4 as a Suppressor for Motility of Ovarian Cancer Cells. TOHOKU J EXP MED 2019;247:59-67. [PMID: 30686809 DOI: 10.1620/tjem.247.59] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]

Tian Y, Han Y, Guo H, Jin H, Sun C, Qi X, Ma L, Bo S. Retracted : Upregulated microRNA‐485 suppresses apoptosis of renal tubular epithelial cells in mice with lupus nephritis via regulating the TGF‐β‐MAPK signaling pathway by inhibiting RhoA expression. J Cell Biochem 2018;119:9154-9167. [DOI: 10.1002/jcb.27178] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 05/24/2018] [Indexed: 12/24/2022]

Nomikou E, Livitsanou M, Stournaras C, Kardassis D. Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases. Cell Mol Life Sci 2018;75:2111-2124. [PMID: 29500478 PMCID: PMC11105751 DOI: 10.1007/s00018-018-2787-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/25/2018] [Accepted: 02/26/2018] [Indexed: 12/15/2022]

Ju JA, Gilkes DM. RhoB: Team Oncogene or Team Tumor Suppressor? Genes (Basel) 2018;9:E67. [PMID: 29385717 PMCID: PMC5852563 DOI: 10.3390/genes9020067] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 01/21/2018] [Accepted: 01/24/2018] [Indexed: 12/31/2022] Open

Horiuchi A, Wang C, Kikuchi N, Osada R, Nikaido T, Konishi I. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 during Cisplatin Treatment in Ovarian Cancer Cells. Biomark Insights 2017. [DOI: 10.1177/117727190600100007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open

Lee P, Wolgemuth CW. Physical Mechanisms of Cancer in the Transition to Metastasis. Biophys J 2017;111:256-66. [PMID: 27410752 DOI: 10.1016/j.bpj.2016.05.046] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 05/20/2016] [Accepted: 05/31/2016] [Indexed: 10/21/2022] Open

Mutant p53 Protein and the Hippo Transducers YAP and TAZ: A Critical Oncogenic Node in Human Cancers. Int J Mol Sci 2017;18:ijms18050961. [PMID: 28467351 PMCID: PMC5454874 DOI: 10.3390/ijms18050961] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 04/11/2017] [Accepted: 04/24/2017] [Indexed: 02/07/2023] Open

Niu Y, Xia Y, Wang J, Shi X. O-GlcNAcylation promotes migration and invasion in human ovarian cancer cells via the RhoA/ROCK/MLC pathway. Mol Med Rep 2017;15:2083-2089. [PMID: 28259907 PMCID: PMC5364967 DOI: 10.3892/mmr.2017.6244] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 11/11/2016] [Indexed: 02/06/2023] Open

Pronina IV, Klimov EA, Burdennyy AM, Beresneva EV, Fridman MV, Ermilova VD, Kazubskaya TP, Karpukhin AV, Braga EA, Loginov VI. Methylation of the genes for the microRNAs miR-129-2 and miR-9-1, changes in their expression, and activation of their potential target genes in clear cell renal cell carcinoma. Mol Biol 2017. [DOI: 10.1134/s0026893316060169] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]

Liu BL, Sun KX, Zong ZH, Chen S, Zhao Y. MicroRNA-372 inhibits endometrial carcinoma development by targeting the expression of the Ras homolog gene family member C (RhoC). Oncotarget 2017;7:6649-64. [PMID: 26673619 PMCID: PMC4872740 DOI: 10.18632/oncotarget.6544] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 11/16/2015] [Indexed: 01/29/2023] Open

Majeski HE, Yang J. The 2016 John J. Abel Award Lecture: Targeting the Mechanical Microenvironment in Cancer. Mol Pharmacol 2016;90:744-754. [PMID: 27742780 PMCID: PMC5118638 DOI: 10.1124/mol.116.106765] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 10/13/2016] [Indexed: 12/14/2022] Open

Menyhárt O, Harami-Papp H, Sukumar S, Schäfer R, Magnani L, de Barrios O, Győrffy B. Guidelines for the selection of functional assays to evaluate the hallmarks of cancer. Biochim Biophys Acta Rev Cancer 2016;1866:300-319. [PMID: 27742530 DOI: 10.1016/j.bbcan.2016.10.002] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/06/2016] [Accepted: 10/08/2016] [Indexed: 01/05/2023]

Haga RB, Ridley AJ. Rho GTPases: Regulation and roles in cancer cell biology. Small GTPases 2016;7:207-221. [PMID: 27628050 PMCID: PMC5129894 DOI: 10.1080/21541248.2016.1232583] [Citation(s) in RCA: 366] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 08/26/2016] [Accepted: 08/29/2016] [Indexed: 02/08/2023] Open

Jiang H, Chen C, Sun Q, Wu J, Qiu L, Gao C, Liu W, Yang J, Jun N, Dong J. The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer. Onco Targets Ther 2016;9:5737-5750. [PMID: 27729799 PMCID: PMC5045906 DOI: 10.2147/ott.s114708] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open

Abstract

Background

Semaphorin 4D (Sema4D) is highly expressed in certain types of tumors and functions in the regulation of tumor angiogenesis and growth. However, it is still not clear regarding the roles of Sema4D in breast cancer. This study was designed to explore the effects of Sema4D on proliferation, cell cycle progression, apoptosis, invasion, migration, tumor growth, and angiogenesis in breast cancer.

Materials and methods

The expression level of Sema4D was investigated in MCF10A, 184A1, HCC1937, MDA-MB-468, MDA-MB-231, Hs578T, BT474, MCF-7, and T47D breast cancer cell lines by Western blotting analysis. Sema4D downregulation or overexpression was established by infection with lentiviruses-encoding Sema4D short hairpin RNA (shRNA) or Sema4D. To evaluate the effects of Sema4D on cell proliferation, cell cycle progression, apoptosis, invasion, and migration of MDA-MB-231 and MDA-MB-468 cells, methods including MTT assay, flow cytometry, wound healing assay, and transwell experiments were applied. BALB/c nude mice were injected with MDA-MB-231 cells, which were respectively infected with lentiviruses-encoding Sema4D, Sema4D shRNA, and GFP, followed by tumor angiogenesis assay.

Results

Sema4D was expressed at higher levels in breast cancer cell lines compared with the normal human breast epithelial cell lines, especially in MDA-MB-231 and MDA-MB-468 cells. Cell proliferation ability was remarkably inhibited in Sema4D downregulated condition, whereas the proportions of cells in the G0/G1 phase and apoptosis increased in MDA-MB-231 and MDA-MB-468 cells. In addition, the invasion and migration abilities of these cells were obviously reduced. Xenograft growth as well as angiogenesis was inhibited when infected with lentiviruses-encoding Sema4D shRNA in vivo.

Conclusion

Downregulation of Sema4D had notable influence on cell proliferation ability, invasion, migration, and apoptosis of both MDA-MB-231 and MDA-MB-468 cells. Furthermore, infection with lentiviruses-encoding Sema4D shRNA obviously inhibited tumor growth and angiogenesis in BALB/c nude mice. Our results showed that Sema4D may represent a novel therapeutic target for human breast cancer.

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Cheng S, Castillo V, Welty M, Eliaz I, Sliva D. Honokiol inhibits migration of renal cell carcinoma through activation of RhoA/ROCK/MLC signaling pathway. Int J Oncol 2016;49:1525-1530. [DOI: 10.3892/ijo.2016.3663] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 08/02/2016] [Indexed: 11/06/2022] Open

Yao J, Gao P, Xu Y, Li Z. α-TEA inhibits the growth and motility of human colon cancer cells via targeting RhoA/ROCK signaling. Mol Med Rep 2016;14:2534-40. [PMID: 27432222 PMCID: PMC4991732 DOI: 10.3892/mmr.2016.5525] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 05/03/2016] [Indexed: 01/01/2023] Open

Choi HJ, Do KH, Park JH, Kim J, Yu M, Park SH, Moon Y. Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug–Activated Gene 1 Counteracts Intestinal Ulcerative Injuries. THE JOURNAL OF IMMUNOLOGY 2016;197:1415-24. [DOI: 10.4049/jimmunol.1501784] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 06/03/2016] [Indexed: 01/07/2023]

Fukushima H, Yasumoto M, Ogasawara S, Akiba J, Kitasato Y, Nakayama M, Naito Y, Ishida Y, Okabe Y, Yasunaga M, Horiuchi H, Sakamoto E, Itadani H, Mizuarai S, Oie S, Yano H. ARHGEF15 overexpression worsens the prognosis in patients with pancreatic ductal adenocarcinoma through enhancing the motility and proliferative activity of the cancer cells. Mol Cancer 2016;15:32. [PMID: 27145964 PMCID: PMC4857279 DOI: 10.1186/s12943-016-0516-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 03/29/2016] [Indexed: 12/12/2022] Open

Abstract

BACKGROUND

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases, associated with a remarkably poor prognosis. However, the molecular mechanisms underlying the development of PDAC remain elusive. The aim of this study was to identify genes whose expressions are correlated with a poor prognosis in PDAC patients, and to unravel the mechanisms underlying the involvement of these genes in the development of the cancer.

METHODS

Global gene expression profiling was conducted in 39 specimens obtained from Japanese patients with PDAC to identify genes whose expressions were correlated with a shorter overall survival. The effect of gene silencing or overexpression of ARHGEF15 in pancreatic cancer cell lines was examined by introducing siRNAs of ARHGEF15 or the ARHGEF15 expression vector. After assessing the effect of ARHGEF15 deregulation on the Rho-family proteins by pull-down assay, wound healing, transwell and cell viability assays were carried out to investigate the cellular phenotypes caused by the perturbation.

RESULTS

The global mRNA expression profiling revealed that overexpression of ARHGEF15, a Rho-specific GEF, was significantly associated with a poor prognosis in patients with PDAC. We also found that the depletion of ARHGEF15 by RNA interference in pancreatic cancer cell lines downregulated the activities of molecules of the Rho signaling pathway, including RhoA, Cdc42 and Rac1. Then, we also showed that ARHGEF15 silencing significantly reduced the motility and viability of the cells, while its overexpression resulted in the development of the opposite phenotype in multiple pancreatic cancer cell lines.

CONCLUSION

These data suggest that upregulation of ARHGEF15 contributes to the development of aggressive PDAC by increasing the growth and motility of the pancreatic cancer cells, thereby worsening the prognosis of these patients. Therefore, ARHGEF15 could serve as a novel therapeutic target in patients with PDAC.

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Affiliation(s)

Hiroto Fukushima Biomarker Research, Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan.
Makiko Yasumoto Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Sachiko Ogasawara Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Jun Akiba Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Yuhei Kitasato Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Masamichi Nakayama Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Yoshiki Naito Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Yusuke Ishida Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Yoshinobu Okabe Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Masafumi Yasunaga Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Hiroyuki Horiuchi Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
Etsuko Sakamoto Biomarker Research, Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
Hiraku Itadani Biomarker Research, Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
Shinji Mizuarai Biomarker Research, Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
Shinji Oie Biomarker Research, Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan
Hirohisa Yano Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan

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Jin SG, Ryu HH, Li SY, Li CH, Lim SH, Jang WY, Jung S. Nogo-A inhibits the migration and invasion of human malignant glioma U87MG cells. Oncol Rep 2016;35:3395-402. [PMID: 27109183 DOI: 10.3892/or.2016.4737] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/05/2016] [Indexed: 11/06/2022] Open

Abstract

Nogo or reticulon-4 (RTN4), also known as neurite outgrowth inhibitor, is a member of the reticulon family of genes. Nogo-A, one of the three isoforms, is enriched in the central nervous system (CNS). The extracellular domain of Nogo-A, Nogo-66, has neurite growth inhibitory activity that is specific for neurons and is mediated by the Nogo receptor. However, most of its functions are not known yet. We investigated whether Nogo-A modulates the migration and invasion of a glioblastoma cell line, as well as the factors that have an effect on Nogo-A. The expression of Nogo-A was evaluated using western blotting and immunohistochemistry in human brain tumor specimens. U87MG cells were transfected with a sense-Nogo-A cDNA construct (U87-Nogo-A cells expressing Nogo-A) and an empty vector (U87MG-E cells not expressing Nogo-A). The migration and invasion abilities of these cells were investigated using simple scratch and Matrigel invasion assays. Morphologic and cytoskeletal changes were documented by confocal microscopy. The proliferation rate was estimated using doubling time assay. The effects of Nogo-A on Rho activity and phosphorylated cofilin were determined by a Rho activity assay and western blotting. Among primary brain tumors, Nogo-A expression was found in a higher percentage of oligodendrogliomas (90.0%) compared with the percentage in the glioblastomas (68.4%). In addition, the percentage in mixed gliomas was 42.9%, while it was not expressed in pituitary adenomas or schwannomas. The migration and invasion abilities of the U87-Nogo-A cells were decreased compared with the control. In the U87-Nogo-A cell line, Rho activity and phosphorylated cofilin expression were also decreased and morphology became more flat in comparison with the U87MG-E cell line. Nogo-A may inhibit the migration and invasion of human malignant glioma cells via the downregulation of RhoA-cofilin signaling.

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Shi K, Gao L, Wang B. Discovering potential cancer driver genes by an integrated network-based approach. MOLECULAR BIOSYSTEMS 2016;12:2921-31. [DOI: 10.1039/c6mb00274a] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]

Ushiku T, Ishikawa S, Kakiuchi M, Tanaka A, Katoh H, Aburatani H, Lauwers GY, Fukayama M. RHOA mutation in diffuse-type gastric cancer: a comparative clinicopathology analysis of 87 cases. Gastric Cancer 2016;19:403-411. [PMID: 25823974 PMCID: PMC4824805 DOI: 10.1007/s10120-015-0493-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 03/13/2015] [Indexed: 02/07/2023]