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Chang IY, Boo HJ, Hyun JW, Yoon SP. The feasible role of soluble E‑cadherin in spheroidogenesis of HCT116 colorectal cancer cells, a candidate biomarker for liquid biopsy. Oncol Lett 2025; 29:245. [PMID: 40182609 PMCID: PMC11967162 DOI: 10.3892/ol.2025.14991] [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: 11/05/2024] [Accepted: 02/21/2025] [Indexed: 04/05/2025] Open
Abstract
Although E-cadherin is known as a tumor suppressor via its effects on cell to cell adhesion, the effects of E-cadherin on malignant transformation have not yet been thoroughly investigated. In the present study, after malignant transformation was induced by spheroid formation in a fetal bovine serum-supplemented environment, the effects of soluble E-cadherin on the spheroidogenesis of colorectal cancer cells were investigated. E-cadherin knock-out (KO) was performed in HCT116 cells, targeting exon 3 of the CDH1 gene. A cell viability assay was performed to determine the proliferation and viability of wild type and CDH1 KO HCT116 cells after treatment with anticancer drugs. Spheroidogenesis was compared with or without exogenous E-cadherin, antibody against the ectodomain of E-cadherin (DECMA-1) and PD98059 treatment. In addition, morphometry, immunocytochemistry and western blotting were performed. Soluble E-cadherin in culture media was measured using an enzyme-linked immunosorbent assay. Firstly, CDH1 KO was confirmed by western blotting. Notably, the proliferation and viability of cells following treatment with 5-fluorouracil, epidermal growth factor receptor inhibitor and src kinase inhibitor were similar between the cell lines. Exogenous E-cadherin or DECMA-1 treatment did not affect spheroidogenesis, although long-term maintenance was slightly disturbed in CDH1 KO spheroids compared with that in wild type spheroids. In addition, E-cadherin was increased in spheroid culture as compared with that in conventional culture. Soluble E-cadherin was increased in a time-dependent manner, particularly in wild type HCT116 cells. PD98059 inhibited ERK activation and enhanced E-cadherin expression in conventional culture without affecting spheroidogenesis. These results suggested that soluble E-cadherin may be considered as a biomarker for colorectal cancer, although exogenous E-cadherin might not have a further role in malignant transformation.
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Affiliation(s)
- In-Youb Chang
- Department of Anatomy, College of Medicine, Chosun University, Gwangju 61452, Republic of Korea
| | - Hye-Jin Boo
- Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Jin Won Hyun
- Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
| | - Sang-Pil Yoon
- Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
- Department of Anatomy, College of Medicine, Jeju National University, Jeju 63243, Republic of Korea
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Han F, Qi G, Li R, Peng J, Yan S, Yuan C, Kong B, Ma H. USP28 promotes PARP inhibitor resistance by enhancing SOX9-mediated DNA damage repair in ovarian cancer. Cell Death Dis 2025; 16:305. [PMID: 40240356 PMCID: PMC12003857 DOI: 10.1038/s41419-025-07647-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 03/31/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025]
Abstract
PARP inhibitor (PARPi) resistance presents a significant challenge in ovarian cancer treatment, necessitating the development of effective therapeutic strategies to overcome this resistance and improve patient outcomes. Our study demonstrated that elevated expression of SRY-box 9 (SOX9) contributes to olaparib resistance in ovarian cancer. Mechanistically, the deubiquitinating enzyme USP28 was identified as a novel interacting partner of SOX9. USP28 inhibited the ubiquitination and subsequent degradation of SOX9, which is mediated by the E3 ubiquitin ligase FBXW7 during olaparib treatment. ChIP-Seq analysis revealed that SOX9 binds to the promoters of key DNA damage repair (DDR) genes (SMARCA4, UIMC1, and SLX4), thereby regulating DDR processes in ovarian cancer. Additionally, USP28 promoted olaparib resistance by stabilizing SOX9 protein and enhancing DNA damage repair. Furthermore, the USP28 specific inhibitor AZ1 reduced SOX9 protein stability and increased the sensitivity of ovarian cancer cells to olaparib. In conclusion, targeted inhibition of USP28 promoted ubiquitination-mediated degradation of SOX9, thereby impairing DNA damage repair capabilities and sensitizing ovarian cancer cells to PARPi. These findings elucidate the underlying mechanisms of PARPi resistance in ovarian cancer and suggest the potential efficacy of combining USP28 inhibitors with PARPi to overcome this resistance.
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Affiliation(s)
- Fang Han
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China
| | - Gonghua Qi
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Rongrong Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Jiali Peng
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Shi Yan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Cunzhong Yuan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China
| | - Hanlin Ma
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.
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Lee Y, Ko D, Yoon J, Kim S. TMEM52B-derived peptides inhibit generation of soluble E-cadherin and EGFR activity to suppress colon cancer growth and early metastasis. J Transl Med 2025; 23:146. [PMID: 40025509 PMCID: PMC11874797 DOI: 10.1186/s12967-025-06075-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/02/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Transmembrane protein 52B (TMEM52B) is a novel gene expressed widely in various normal human tissues; however, the biological function of TMEM52B in cancer remains largely unknown. Previously, we demonstrated that TMEM52B is a novel modulator of E-cadherin and EGFR activity, and that it has tumor suppressor-like activity using both experimental and clinical analyses. Here, we hypothesized that the extracellular domain (ECD) of TMEM52B may exert tumor-suppressing activity. METHODS We designed and evaluated the therapeutic potential of TMEM52B ECD-derived peptides in vitro and in vivo. The molecular mechanisms underlying the anti-cancer activity of the peptides were explored. RESULTS TMEM52B ECD-derived peptides reduced cancer cell survival, invasion, and anchorage-independent growth, which was accompanied by decreased phosphorylation of ERK1/2 and AKT. The peptides maintained intact E-cadherin at organized cell-cell junctions, leading to reduced β-catenin activity. They also inhibited generation of soluble E-cadherin and activation of EGFR by binding directly to the E-cadherin ECD and interfering with the interaction between soluble E-cadherin and EGFR. Peptides fused to the Fc domain of human IgG1 efficiently inhibited tumor growth in a colon cancer xenograft model and reduced survival of circulating tumor cells in an early metastasis model. CONCLUSIONS These results strongly suggest that TMEM52B ECD-derived peptides could provide a platform for the development of novel anti-cancer therapeutics and furnish a useful tool for exploring the function of TMEM52B in modulating the interplay between E-cadherin and EGFR.
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Affiliation(s)
- Yunhee Lee
- Korea Research Institute of Bioscience and Biotechnology, Microbiome Convergence Research Center, 125 Gwahak-ro, Yuseong-gu, Daejon, 34141, Korea
| | - Dongjoon Ko
- Korea Research Institute of Bioscience and Biotechnology, Microbiome Convergence Research Center, 125 Gwahak-ro, Yuseong-gu, Daejon, 34141, Korea
- Department of Functional Genomics, Korea University of Science and Technology, Daejon, 34113, Korea
| | - Junghwa Yoon
- Korea Research Institute of Bioscience and Biotechnology, Microbiome Convergence Research Center, 125 Gwahak-ro, Yuseong-gu, Daejon, 34141, Korea
| | - Semi Kim
- Korea Research Institute of Bioscience and Biotechnology, Microbiome Convergence Research Center, 125 Gwahak-ro, Yuseong-gu, Daejon, 34141, Korea.
- Department of Functional Genomics, Korea University of Science and Technology, Daejon, 34113, Korea.
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He X, Wang G, Wang Y, Zhang C. Matrine Enhances the Antitumor Efficacy of Chidamide in CTCL by Promoting Apoptosis. Recent Pat Anticancer Drug Discov 2025; 20:223-231. [PMID: 38571359 DOI: 10.2174/0115748928289036240318040756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND Cutaneous T-cell Lymphoma (CTCL) is a rare group of non-Hodgkin lymphoma originating from the skin, which is characterized by T-cell lymphoproliferative disorders. Chidamide, a Chinese original antineoplastic agent with independent intellectual property rights, and matrine, an extract of Chinese herbal medicine, both have been reported to exert effects on the treatment of tumors individually. However, chidamide combined with matrine has not been tested for the treatment of CTCL. METHODS Both HH and Hut78 CTCL cell lines were treated with chidamide (0.4 μmol/L), matrine (0.6 g/L), or chidamide combined with matrine for 24, 48, and 72 h. Cell viability was estimated by MTS assay at each time point. Flow cytometry was then conducted to detect cell apoptosis. The exact mechanism of chidamide combined with matrine on CTCL cells was detected by Western blotting and further validated in xenograft models of NOD/SCID mice. RESULTS AND DISCUSSION Compared to the single drug, chidamide combined with matrine showed a more significant effect on proliferation inhibition and apoptosis induction on CTCL cells both in vitro and in vivo. The results from the in vitro and in vivo studies suggested that matrine could enhance the anti-tumor effect of chidamide by increasing the protein expression of cleaved caspase- 3 and decreasing the expression of E-cadherin, NF-κB, p-Bad, and Bcl-2 to activate apoptosis. CONCLUSION Our data have demonstrated chidamide combined with matrine to exhibit elevated antitumor activity in both CTCL cells and xenograft models of NOD/SCID mice, which may be a potential treatment option for CTCL.
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Affiliation(s)
- Xinglan He
- Department of Dermatology, Peking University Third Hospital, Beijing, China
| | - Guanyu Wang
- Department of Dermatology, Peking University Third Hospital, Beijing, China
| | - Yimeng Wang
- Department of Dermatology, Peking University Third Hospital, Beijing, China
| | - Chunlei Zhang
- Department of Dermatology, Peking University Third Hospital, Beijing, China
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Sarker DB, Xue Y, Mahmud F, Jocelyn JA, Sang QXA. Interconversion of Cancer Cells and Induced Pluripotent Stem Cells. Cells 2024; 13:125. [PMID: 38247819 PMCID: PMC10814385 DOI: 10.3390/cells13020125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/23/2024] Open
Abstract
Cancer cells, especially cancer stem cells (CSCs), share many molecular features with induced pluripotent stem cells (iPSCs) that enable the derivation of induced pluripotent cancer cells by reprogramming malignant cells. Conversely, normal iPSCs can be converted into cancer stem-like cells with the help of tumor microenvironment components and genetic manipulation. These CSC models can be utilized in oncogenic initiation and progression studies, understanding drug resistance, and developing novel therapeutic strategies. This review summarizes the role of pluripotency factors in the stemness, tumorigenicity, and therapeutic resistance of cancer cells. Different methods to obtain iPSC-derived CSC models are described with an emphasis on exposure-based approaches. Culture in cancer cell-conditioned media or cocultures with cancer cells can convert normal iPSCs into cancer stem-like cells, aiding the examination of processes of oncogenesis. We further explored the potential of reprogramming cancer cells into cancer-iPSCs for mechanistic studies and cancer dependencies. The contributions of genetic, epigenetic, and tumor microenvironment factors can be evaluated using these models. Overall, integrating iPSC technology into cancer stem cell research holds significant promise for advancing our knowledge of cancer biology and accelerating the development of innovative and tailored therapeutic interventions.
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Affiliation(s)
- Drishty B. Sarker
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Yu Xue
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Faiza Mahmud
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Jonathan A. Jocelyn
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Qing-Xiang Amy Sang
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
- Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306-4380, USA
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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Bernegger S, Jarzab M, Wessler S, Posselt G. Proteolytic Landscapes in Gastric Pathology and Cancerogenesis. Int J Mol Sci 2022; 23:2419. [PMID: 35269560 PMCID: PMC8910283 DOI: 10.3390/ijms23052419] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 02/01/2023] Open
Abstract
Gastric cancer is a leading cause of cancer-related death, and a large proportion of cases are inseparably linked to infections with the bacterial pathogen and type I carcinogen Helicobacter pylori. The development of gastric cancer follows a cascade of transformative tissue events in an inflammatory environment. Proteases of host origin as well as H. pylori-derived proteases contribute to disease progression at every stage, from chronic gastritis to gastric cancer. In the present article, we discuss the importance of (metallo-)proteases in colonization, epithelial inflammation, and barrier disruption in tissue transformation, deregulation of cell proliferation and cell death, as well as tumor metastasis and neoangiogenesis. Proteases of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase domain-containing protein (ADAM) families, caspases, calpain, and the H. pylori proteases HtrA, Hp1012, and Hp0169 cleave substrates including extracellular matrix molecules, chemokines, and cytokines, as well as their cognate receptors, and thus shape the pathogenic microenvironment. This review aims to summarize the current understanding of how proteases contribute to disease progression in the gastric compartment.
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Affiliation(s)
- Sabine Bernegger
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
| | - Miroslaw Jarzab
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
| | - Silja Wessler
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
- Cancer Cluster Salzburg and Allergy Cancer BioNano Research Centre, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria
| | - Gernot Posselt
- Division of Microbiology, Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria; (S.B.); (M.J.); (S.W.)
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Wang J, Yokoyama Y, Hirose H, Shimomura Y, Bonkobara S, Itakura H, Kouda S, Morimoto Y, Minami K, Takahashi H, Shibata S, Kobayashi S, Uemura M, Tanaka S, Wu X, Tanaka S, Mori M, Yamamoto H. Functional assessment of miR‑1291 in colon cancer cells. Int J Oncol 2022; 60:13. [PMID: 34981812 PMCID: PMC8759348 DOI: 10.3892/ijo.2022.5303] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
miR‑1291 exerts an anti‑tumor effect in a subset of human carcinomas, including pancreatic cancer. However, its role in colorectal cancer (CRC) is largely unknown. In the present study, the expression and effect of miR‑1291 in CRC cells was investigated. It was identified that miR‑1291 significantly suppressed the proliferation, invasion, cell mobility and colony formation of CRC cells. Additionally, miR‑1291 induced cell apoptosis. A luciferase reporter assay revealed that miR‑1291 directly bound the 3'‑untranslated region sequence of doublecortin‑like kinase 1 (DCLK1). miR‑1291 also suppressed DCLK1 mRNA and protein expression in HCT116 cells that expressed DCLK1. Furthermore, miR‑1291 suppressed cancer stem cell markers BMI1 and CD133, and inhibited sphere formation. The inhibitory effects on sphere formation, invasion and mobility in HCT116 cells were also explored and verified using DCLK1 siRNAs. Furthermore, miR‑1291 induced CDK inhibitors p21WAF1/CIP1 and p27KIP1 in three CRC cell lines, and the overexpression of DCLK1 in HCT116 cells led to a decrease of p21WAF1/CIP1 and p27KIP1. Intravenous administration of miR‑1291 loaded on the super carbonate apatite delivery system significantly inhibited tumor growth in the DLD‑1 xenograft mouse model. Additionally, the resultant tumors exhibited significant upregulation of the p21WAF1/CIP1 and p27KIP1 protein with treatment of miR‑1291. Taken together, the results indicated that miR‑1291 served an anti‑tumor effect by modulating multiple functions, including cancer stemness and cell cycle regulation. The current data suggested that miR‑1291 may be a promising nucleic acid medicine against CRC.
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Affiliation(s)
- Jiaqi Wang
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuhki Yokoyama
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Haruka Hirose
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuki Shimomura
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Saki Bonkobara
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Itakura
- Department of Surgery and Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Shihori Kouda
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yoshihiro Morimoto
- Department of Surgery and Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kazumasa Minami
- Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidekazu Takahashi
- Department of Surgery and Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Satoshi Shibata
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Shogo Kobayashi
- Department of Surgery and Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Mamoru Uemura
- Department of Surgery and Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Susumu Tanaka
- First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, Suita, Osaka 565-0871, Japan
| | - Xin Wu
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
- Department of Hepato-Billiary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Masaki Mori
- Tokai University, Graduate School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Hirofumi Yamamoto
- Department of Molecular Pathology, Division of Health Sciences, Osaka University, Suita, Osaka 565-0871, Japan
- Department of Surgery and Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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9
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Novoa Díaz MB, Carriere PM, Martín MJ, Calvo N, Gentili C. Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells. World J Gastroenterol 2021; 27:7025-7040. [PMID: 34887626 PMCID: PMC8613645 DOI: 10.3748/wjg.v27.i41.7025] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/26/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of mortality from malignant diseases worldwide. In general terms, CRC presents high heterogeneity due to the influence of different genetic and environmental factors; also, the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells, known together as the tumor microenvironment (TME). Bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine factors. Parathyroid hormone-related peptide (PTHrP) is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological processes. It exerts its effects as a paracrine/autocrine factor, although its mode of action is mainly paracrine. It has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral hypercalcemia. Eight years ago, when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors, the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited, and no articles had been published regarding to the paracrine action of PTHrP in CRC cells. Based on this and on our previous findings regarding the role of PTH in CRC cells, our purpose in recent years has been to explore the role of PTHrP in CRC. We analyzed the behavior of CRC cells treated with exogenous PTHrP, focalizing in the study of the following events: Survival, cell cycle progression and proliferation, migration, chemoresistance, tumor-associated angiogenesis, epithelial to mesenchymal transition program and other events also associated with invasion, such us the induction of cancer stem cells features. This work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressive phenotype of CRC cells and the molecular mechanisms involved in these processes. Recently, we found that this cytokine induces this malignant behavior not only by its direct action on these intestinal cells but also through its influence on cells derived from TME, promoting a communication between CRC cells and surrounding cells that contributes to the molecular and morphological changes observed in CRC cells. These investigations establish the basis for our next studies in order to address the clinical applicability of our findings. Recognizing the factors and mechanisms that promote invasion in CRC cells, evasion to the cytotoxic effects of current CRC therapies and thus metastasis is decisive for the identification of new markers with the potential to improve early diagnosis and/or to predict prognosis, to predetermine drug resistance and to provide treatment guidelines that include targeted therapies for this disease.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Matías Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)- INQUISUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Natalia Calvo
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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10
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Wu Y, Liu H, Gong Y, Zhang B, Chen W. ANKRD22 enhances breast cancer cell malignancy by activating the Wnt/β-catenin pathway via modulating NuSAP1 expression. Bosn J Basic Med Sci 2021; 21:294-304. [PMID: 32651974 PMCID: PMC8112564 DOI: 10.17305/bjbms.2020.4701] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is one of the most prevalent malignancies in women worldwide. Although great advancements have been achieved in the diagnosis and treatment of breast cancer, the prognosis of patients with breast cancer is still poor due to distal recurrence and metastasis after surgery. This study aimed to assess the role of ankyrin repeat domain 22 (ANKRD22) in the progression of breast cancer and investigate the molecular mechanism. Using immunohistochemistry, we demonstrated that the expression level of ANKRD22 in human breast cancer tissues was significantly higher than that in normal breast tissues. ANKRD22 knockdown inhibited the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of breast cancer cells, as confirmed by BrdU, colony formation, transwell, and immunoblot assays. Immunoblot assays further indicated that ANKRD22 regulated the expression of nucleolar and spindle-associated protein 1 (NuSAP1) and then caused the activation of Wnt/β-catenin signaling pathway. Moreover, overexpression of NUSAP1 reversed the inhibitory effects of ANKRD22 knockdown on the proliferation, invasion, and EMT of breast cancer cells. In summary, this study demonstrated that ANKRD22 enhanced breast cancer cell malignancy by activating the Wnt/β-catenin pathway via modulating NuSAP1 expression, which might shed light on new therapeutic approaches for breast cancer.
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Affiliation(s)
- Yange Wu
- Department of Pathology, Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, China
| | - Hongxia Liu
- Department of Pathology, Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, China
| | - Yufeng Gong
- Department of Pathology, Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, China
| | - Bo Zhang
- Department of Pathology, Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, China
| | - Wenxiu Chen
- Department of Pathology, Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, China
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11
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Liu Y, Wu H, Luo T, Luo Q, Meng Z, Shi Y, Li F, Liu M, Peng X, Liu J, Xu C, Tang W. The SOX9-MMS22L Axis Promotes Oxaliplatin Resistance in Colorectal Cancer. Front Mol Biosci 2021; 8:646542. [PMID: 34124145 PMCID: PMC8191464 DOI: 10.3389/fmolb.2021.646542] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 04/20/2021] [Indexed: 12/12/2022] Open
Abstract
Background Colorectal cancer (CRC) is estimated to be one of the most common cancers and the leading cause of cancer-related death worldwide. SOX9 is commonly overexpressed in CRC and participates in drug resistance. In addition, DNA damage repair confers resistance to anticancer drugs. However, the correlation between DNA damage repair and high SOX9 expression is still unclear. In this study, we aimed to investigate the function and the specific underlying mechanism of the SOX9-dependent DNA damage repair pathway in CRC. Methods The expression levels of SOX9 and MMS22L in CRC were examined by immunohistochemistry (IHC) and TCGA analysis. RNA sequencing was conducted in RKO SOX9-deficient cells and RKO shControl cells. Mechanistic studies were performed in CRC cells by modulating SOX9 and MMS22L expression, and we evaluated drug sensitivity and DNA damage repair signaling events. In addition, we investigated the effect of oxaliplatin in tumors with SOX9 overexpression and low expression of MMS22L in vivo. Results Our study showed that SOX9 has a higher expression level in CRC tissues than in normal tissues and predicts poor prognosis in CRC patients. Overexpression and knockdown of SOX9 were associated with the efficacy of oxaliplatin. In addition, SOX9 activity was enriched in the DNA damage repair pathway via regulation of MMS22L expression and participation in DNA double-strand break repair. SOX9 was upregulated and formed a complex with MMS22L, which promoted the nuclear translocation of MMS22L upon oxaliplatin treatment. Moreover, the xenograft assay results showed that oxaliplatin abrogated tumor growth from cells with MMS22L downregulation in mice. Conclusions In CRC, activation of the SOX9-MMS22L-dependent DNA damage pathway is a core pathway regulating oxaliplatin sensitivity. Targeting this pathway in oxaliplatin-resistant CRC cells is a promising therapeutic option.
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Affiliation(s)
- Yiqiang Liu
- Department of Experimental Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China.,Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Hong Wu
- Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Tao Luo
- Department of Experimental Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Qiyu Luo
- Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ziyu Meng
- Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ying Shi
- Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Feifei Li
- Department of Experimental Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China.,Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Mingxin Liu
- Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xinhao Peng
- Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Junjie Liu
- Department of Experimental Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Chuan Xu
- Integrative Cancer Center and Cancer Clinical Research Center, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Weizhong Tang
- Department of Experimental Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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12
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Panda M, Tripathi SK, Biswal BK. SOX9: An emerging driving factor from cancer progression to drug resistance. Biochim Biophys Acta Rev Cancer 2021; 1875:188517. [PMID: 33524528 DOI: 10.1016/j.bbcan.2021.188517] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/20/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
Dysregulation of transcription factors is one of the common problems in the pathogenesis of human cancer. Among them, SOX9 is one of the critical transcription factors involved in various diseases, including cancer. The expression of SOX9 is regulated by microRNAs (miRNAs), methylation, phosphorylation, and acetylation. Interestingly, SOX9 acts as a proto-oncogene or tumor suppressor gene, relying upon kinds of cancer. Recent studies have reported the critical role of SOX9 in the regulation of the tumor microenvironment (TME). Additionally, activation of SOX9 signaling or SOX9 regulated signaling pathways play a crucial role in cancer development and progression. Accumulating evidence also suggests that SOX9 acquires stem cell features to induce epithelial-mesenchymal transition (EMT). Moreover, SOX9 has been broadly studied in the field of cancer stem cell (CSC) and EMT in the last decades. However, the link between SOX9 and cancer drug resistance has only recently been discovered. Furthermore, its differential expression could be a potential biomarker for tumor prognosis and progression. This review outlined the various biological implications of SOX9 in cancer progression and cancer drug resistance and elucidated its signaling network, which could be a potential target for designing novel anticancer drugs.
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Affiliation(s)
- Munmun Panda
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Surya Kant Tripathi
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India
| | - Bijesh K Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha 769008, India.
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13
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He L, Bhat K, Duhacheck-Muggy S, Ioannidis A, Zhang L, Nguyen NT, Moatamed NA, Pajonk F. Tumor necrosis factor receptor signaling modulates carcinogenesis in a mouse model of breast cancer. Neoplasia 2020; 23:197-209. [PMID: 33383310 PMCID: PMC7779542 DOI: 10.1016/j.neo.2020.12.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/18/2020] [Accepted: 12/21/2020] [Indexed: 12/25/2022] Open
Abstract
Pro-inflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of pro-inflammatory cytokine TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both obesity and in the response of tissues to radiation, 2 known risk factors for the development of breast cancer. Here, we demonstrated the loss of one TNFR2 allele led to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal end buds. Furthermore, loss of one TNFR2 allele increased the incidence of breast cancer in MMTV-Wnt1 mice and resulted in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-κB signaling pathway and autocrine production of TNFα. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression. These findings unravel the imbalances in TNFR signaling promote the development and progression of breast cancer, indicating that selective agonists of TNFR2 could potentially modulate the risk for breast cancer in high-risk populations.
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Affiliation(s)
- Ling He
- Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Kruttika Bhat
- Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Sara Duhacheck-Muggy
- Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Angeliki Ioannidis
- Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Le Zhang
- Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Nhan T Nguyen
- Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Neda A Moatamed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Frank Pajonk
- Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
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14
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Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment. Cancers (Basel) 2020; 12:cancers12092605. [PMID: 32933095 PMCID: PMC7563523 DOI: 10.3390/cancers12092605] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) causes a high number (more than 800,000) of deaths worldwide each year. Better methods for early diagnosis and the development of strategies to enhance the efficacy of the therapeutic approaches used to complement or substitute surgical removal of the tumor are urgently needed. Currently available pharmacological armamentarium provides very moderate benefits to patients due to the high resistance of tumor cells to respond to anticancer drugs. The present review summarizes and classifies into seven groups the cellular and molecular mechanisms of chemoresistance (MOC) accounting for the failure of CRC response to the pharmacological treatment. Abstract The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).
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15
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Serafim Junior V, Fernandes GMDM, Oliveira-Cucolo JGD, Pavarino EC, Goloni-Bertollo EM. Role of Tropomyosin-related kinase B receptor and brain-derived neurotrophic factor in cancer. Cytokine 2020; 136:155270. [PMID: 32911446 DOI: 10.1016/j.cyto.2020.155270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023]
Abstract
The tropomyosin-related kinase B (TrkB) receptor is a member of the neurotrophic tyrosine kinase receptors family and, together with the brain-derived neurotrophic factor (BDNF), plays an important role in the development of breast cancer, lung cancer, neuroblastoma, colorectal cancer, leukemia, cervical cancer, gallbladder cancer, gastric cancer, kidney cancer, Ewing's sarcoma, esophageal cancer, and head and neck cancer. Overexpression of these two factors has been associated with increased processes involved in carcinogenesis, such as invasion, migration, epithelial-mesenchymal transition (EMT), angiogenesis, metastasis, cell proliferation, resistance to apoptosis, resistance to cell death due to loss of adhesion (anoikis), activation of cell proliferation pathways, regulation of tumor suppressor genes, and drug resistance, and is related to advanced clinical stage. Inhibition of the TrkB/BDNF axis using drugs in phase 1 studies, approved drugs, and small interfering RNA (siRNA) are promising strategies for the treatment of various malignant tumors in addition to increasing the sensitivity of cells resistant to chemotherapy, improving the effectiveness of drugs without increasing toxicity. Another factor related to poor cancer prognosis is the presence of cancer stem cells, having effects similar to the high expression of the TrkB/BDNF axis, on cancer. This review aimed to show the role of the TrkB/BDNF axis in several types of cancer, its possible use as a prognostic biomarker, the effects of inhibiting this axis, and its role in the cancer stem cells.
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Affiliation(s)
- Vilson Serafim Junior
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Glaucia Maria de Mendonça Fernandes
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Juliana Garcia de Oliveira-Cucolo
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Erika Cristina Pavarino
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Eny Maria Goloni-Bertollo
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil.
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16
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Qian Y, Wu X, Yokoyama Y, Okuzaki D, Taguchi M, Hirose H, Wang J, Hata T, Inoue A, Hiraki M, Ohtsuka M, Takahashi H, Haraguchi N, Mizushima T, Tanaka S, Mori M, Yamamoto H. E-cadherin-Fc chimera protein matrix enhances cancer stem-like properties and induces mesenchymal features in colon cancer cells. Cancer Sci 2019; 110:3520-3532. [PMID: 31505062 PMCID: PMC6825015 DOI: 10.1111/cas.14193] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 08/23/2019] [Accepted: 08/30/2019] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSC) are a subpopulation of tumor cells with properties of high tumorigenicity and drug resistance, which lead to recurrence and poor prognosis. Although a better understanding of CSC is essential for developing cancer therapies, scarcity of the CSC population has hindered such analyses. The aim of the present study was to elucidate whether the E-cadherin-Fc chimera protein (E-cad-Fc) enhances cancer stem-like properties because studies show that soluble E-cadherin stimulates human epithelial growth factor receptor (EGFR) and downstream signaling pathways that are reported to play a crucial role in CSC. For this purpose, we used ornithine decarboxylase (ODC)-degron-transduced (Degron(+)) KM12SM cells as a CSC model that retains relatively low CSC properties. Compared to cultures without E-cad-Fc treatment, we found that E-cad-Fc treatment further suppressed proteasome activity and largely enhanced cancer stem-like properties of ODC-degron-transduced KM12SM cells. These results include increased expression of stem cell markers Lgr5, Bmi-1, SOX9, CD44, and CD44v9, aldehyde dehydrogenase (ALDH), and enhancement of robust spheroid formation, and chemoresistance to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP). These effects could be attributed to activation of the EGFR pathway as identified by extensive phosphorylation of EGFR, ERK, PI3K, AKT, and mTOR. In SW480 cells, E-cad-Fc matrix induced some CSC markers such as CD44v9 and ALDH. We also found that E-cad-Fc matrix showed high efficiency of inducing mesenchymal changes in colon cancer cells. Our data suggest that the E-cad-Fc matrix may enhance CSC properties such as enhancement of chemoresistance and sphere formation.
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Affiliation(s)
- Yamin Qian
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Xin Wu
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Yuhki Yokoyama
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Daisuke Okuzaki
- Genome Information Research CenterResearch Institute for Microbial DiseasesOsaka UniversityOsakaJapan
| | - Mai Taguchi
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Haruka Hirose
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Jiaqi Wang
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Tsuyoshi Hata
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Akira Inoue
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Masayuki Hiraki
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Masahisa Ohtsuka
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Hidekazu Takahashi
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Naotsugu Haraguchi
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Tsunekazu Mizushima
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Shinji Tanaka
- Department of Molecular OncologyGraduate School of MedicineTokyo Medical and Dental UniversityTokyoJapan
| | - Masaki Mori
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Hirofumi Yamamoto
- Department of Molecular PathologyDivision of Health SciencesGraduate School of MedicineOsaka UniversityOsakaJapan
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
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