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Jia H, Wei J, Zheng W, Li Z. The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance. J Transl Med 2025; 23:583. [PMID: 40414839 DOI: 10.1186/s12967-025-06595-z] [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: 02/24/2025] [Accepted: 05/08/2025] [Indexed: 05/27/2025] Open
Abstract
Cancer stem cells (CSCs) constitute a small yet crucial subgroup in tumors, known for their capacity to self-renew, differentiate, and promote tumor growth, metastasis, and resistance to therapy. These characteristics position CSCs as significant factors in tumor recurrence and unfavorable clinical results, emphasizing their role as targets for therapy. Autophagy, an evolutionarily preserved cellular mechanism for degradation and recycling, has a complex function in cancer by aiding cell survival during stress and preserving balance by eliminating damaged organelles and proteins. Although autophagy can hinder tumor growth by reducing genomic instability, it also aids tumor advancement, particularly in harsh microenvironments, highlighting its dual characteristics. Recent research has highlighted the complex interactions between autophagy and CSCs, showing that autophagy governs CSC maintenance, boosts survival, and aids in resistance to chemotherapy and radiotherapy. On the other hand, in specific situations, autophagy may restrict CSC growth by increasing differentiation or inducing cell death. These intricate interactions offer both obstacles and possibilities for therapeutic intervention. Pharmacological modulation of autophagy, via inhibitors like chloroquine or by enhancing autophagy when advantageous, has demonstrated potential in making CSCs more responsive to standard treatments. Nonetheless, applying these strategies in clinical settings necessitates a better understanding of context-dependent autophagy dynamics and the discovery of dependable biomarkers indicating autophagic activity in CSCs. Progressing in this area might unveil novel, accurate strategies to tackle therapy resistance, lessen tumor recurrence, and ultimately enhance patient outcomes.
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Affiliation(s)
- Haiqing Jia
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China
| | - Jing Wei
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China
| | - Wei Zheng
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China.
| | - Zhuo Li
- Department of Gynecology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 xiaoheyan road, Shenyang, 110042, China.
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Xu Z, Liu R, Ke H, Xu F, Yang P, Zhang W, Zhan Y, Zhao Z, Xiao F. ATP6V1D drives hepatocellular carcinoma stemness and progression via both lysosome acidification-dependent and -independent mechanisms. Autophagy 2025; 21:513-529. [PMID: 39316516 PMCID: PMC11849949 DOI: 10.1080/15548627.2024.2406186] [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: 05/15/2024] [Revised: 09/08/2024] [Accepted: 09/16/2024] [Indexed: 09/26/2024] Open
Abstract
Metabolic reprogramming is pivotal in cancer stem cell (CSC) self-renewal. However, the intricate regulatory mechanisms governing the crosstalk between metabolic reprogramming and liver CSCs remain elusive. Here, using a metabolic CRISPR-Cas9 knockout screen, we identify ATP6V1D, a subunit of the vacuolar-type H+-translocating ATPase (V-ATPase), as a key metabolic regulator of hepatocellular carcinoma (HCC) stemness. Elevated ATP6V1D expression correlates with poor clinical outcomes in HCC patients. ATP6V1D knockdown inhibits HCC stemness and malignant progression both in vitro and in vivo. Mechanistically, ATP6V1D enhances HCC stemness and progression by maintaining macroautophagic/autophagic flux. Specifically, ATP6V1D not only promotes lysosomal acidification, but also enhances the interaction between CHMP4B and IST1 to foster ESCRT-III complex assembly, thereby facilitating autophagosome-lysosome fusion to maintain autophagic flux. Moreover, silencing CHMP4B or IST1 attenuates HCC stemness and progression. Notably, low-dose bafilomycin A1 targeting the V-ATPase complex shows promise as a potential therapeutic strategy for HCC. In conclusion, our study highlights the critical role of ATP6V1D in driving HCC stemness and progression via the autophagy-lysosomal pathway, providing novel therapeutic targets and approaches for HCC treatment.Abbreviations: 3-MA: 3-methyladenine; ANT: adjacent normal liver tissues; ATP6V1D: ATPase H+ transporting V1 subunit D; BafA1: bafilomycin A1; CHMP: charged multivesicular body protein; co-IP: co-immunoprecipitation; CSC: cancer stem cell; ESCRT: endosomal sorting complex required for transport; HCC: hepatocellular carcinoma; IF: immunofluorescence; IHC: immunohistochemical; LCSCs: liver cancer stem cells; qRT-PCR: quantitative real time PCR; V-ATPase: vacuolar-type H+- translocating ATPase; WB: western blot.
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Affiliation(s)
- Zhijie Xu
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- The Fifth Affiliated Hospital, Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, Zhuhai, Guangdong Province, China
- Department of Gastroenterology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Ruiyang Liu
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- The Fifth Affiliated Hospital, Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, Zhuhai, Guangdong Province, China
| | - Haoying Ke
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- The Fifth Affiliated Hospital, Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, Zhuhai, Guangdong Province, China
| | - Fuyuan Xu
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- The Fifth Affiliated Hospital, Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, Zhuhai, Guangdong Province, China
| | - Pengfei Yang
- Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Weiyu Zhang
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- The Fifth Affiliated Hospital, Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, Zhuhai, Guangdong Province, China
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Yi Zhan
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- The Fifth Affiliated Hospital, Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, Zhuhai, Guangdong Province, China
| | - Zhiju Zhao
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Fei Xiao
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
- The Fifth Affiliated Hospital, Guangdong-Hong Kong-Macao University Joint of Interventional Medicine, Zhuhai, Guangdong Province, China
- State Key Laboratory of Anti-Infective Drug Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Kashi Guangdong Institute of Science and Technology, The First People’s Hospital of Kashi, Kashi, Xinjiang Uygur Autonomous Region, China
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Hsu TW, Wang WY, Chen HA, Wang TH, Su CM, Liao PH, Chen A, Tsai KY, Kokotos G, Kuo CC, Chiu CF, Su YH. FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma. Cancer Metab 2025; 13:7. [PMID: 39930542 PMCID: PMC11809001 DOI: 10.1186/s40170-025-00377-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC. METHODS We investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine-resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine-resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259. RESULTS We observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3'untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer. CONCLUSION Our results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy.
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Affiliation(s)
- Tung-Wei Hsu
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Wan-Yu Wang
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Hsin-An Chen
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Surgery, Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tzu-Hsuan Wang
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Chih-Ming Su
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Surgery, Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Po-Hsiang Liao
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Alvin Chen
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Kuei-Yen Tsai
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Surgery, Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - George Kokotos
- Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece
| | - Cheng-Chin Kuo
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
- Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan, Taiwan
| | - Ching-Feng Chiu
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Yen-Hao Su
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
- Department of Surgery, Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan.
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Metabolic and Weight Management Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
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Pei S, Zhang D, Li Z, Liu J, Li Z, Chen J, Xie Z. The Role of the Fox Gene in Breast Cancer Progression. Int J Mol Sci 2025; 26:1415. [PMID: 40003882 PMCID: PMC11855465 DOI: 10.3390/ijms26041415] [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: 11/26/2024] [Revised: 01/25/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Forkhead box (FOX) genes are a family of transcription factors that participate in many biological activities, from early embryogenesis to the formation of organs, and from regulation of glucose metabolism to regulation of longevity. Given the extensive influence in the multicellular process, FOX family proteins are responsible for the progression of many types of cancers, especially lung cancer, breast cancer, prostate cancer, and other cancers. Breast cancer is the most common cancer among women, and 2.3 million women were diagnosed in 2020. So, various drugs targeting the FOX signaling pathway have been developed to inhibit breast cancer progression. While the role of the FOX family gene in cancer development has not received enough attention, discovering more potential drugs targeting the FOX signaling pathway is urgently demanded. Here, we review the main members in the FOX gene family and summarize their signaling pathway, including the regulation of the FOX genes and their effects on breast cancer progression. We hope this review will emphasize the understanding of the role of the FOX gene in breast cancer and inspire the discovery of effective anti-breast cancer medicines targeting the FOX gene in the future.
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Affiliation(s)
- Shaoxuan Pei
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Dechun Zhang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Zhuohan Li
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Jinkai Liu
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Ziyi Li
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Jianrui Chen
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
- Medical Department, Queen Mary School, Nanchang University, Nanchang 330031, China
| | - Zhenzhen Xie
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (S.P.); (D.Z.); (Z.L.); (J.L.); (Z.L.); (J.C.)
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Peng X, Zheng J, Liu T, Zhou Z, Song C, Zhang D, Zhang X, Huang Y. DNA Methylation-Based Diagnosis and Treatment of Breast Cancer. Curr Cancer Drug Targets 2025; 25:26-37. [PMID: 38441008 DOI: 10.2174/0115680096278978240204162353] [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: 10/01/2023] [Revised: 01/01/2024] [Accepted: 01/12/2024] [Indexed: 03/06/2024]
Abstract
DNA methylation is a key epigenetic modifier involved in tumor formation, invasion, and metastasis. The development of breast cancer is a complex process, and many studies have now confirmed the involvement of DNA methylation in breast cancer. Moreover, the number of genes identified as aberrantly methylated in breast cancer is rapidly increasing, and the accumulation of epigenetic alterations becomes a chronic factor in the development of breast cancer. The combined effects of external environmental factors and the internal tumor microenvironment promote epigenetic alterations that drive tumorigenesis. This article focuses on the relevance of DNA methylation to breast cancer, describing the role of detecting DNA methylation in the early diagnosis, prediction, progression, metastasis, treatment, and prognosis of breast cancer, as well as recent advances. The reversibility of DNA methylation is utilized to target specific methylation aberrant promoters as well as related enzymes, from early prevention to late targeted therapy, to understand the journey of DNA methylation in breast cancer with a more comprehensive perspective. Meanwhile, methylation inhibitors in combination with other therapies have a wide range of prospects, providing hope to drug-resistant breast cancer patients.
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Affiliation(s)
- Xintong Peng
- School of Clinical Medicine, Affiliated Weifang Medical University, Weifang, China
| | - Jingfan Zheng
- School of Clinical Medicine, Affiliated Weifang Medical University, Weifang, China
| | - Tianzi Liu
- School of Clinical Medicine, Affiliated Weifang Medical University, Weifang, China
| | - Ziwen Zhou
- School of Clinical Medicine, Affiliated Weifang Medical University, Weifang, China
| | - Chen Song
- School of Clinical Medicine, Affiliated Weifang Medical University, Weifang, China
| | - Danyan Zhang
- School of Clinical Medicine, Affiliated Weifang Medical University, Weifang, China
| | - Xinlong Zhang
- School of Clinical Medicine, Affiliated Weifang Medical University, Weifang, China
| | - Yan Huang
- Department of Oncology, Affiliated Hospital of Weifang Medical University, Weifang, China
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Alnefaie GO. A review of the complex interplay between chemoresistance and lncRNAs in lung cancer. J Transl Med 2024; 22:1109. [PMID: 39639388 PMCID: PMC11619437 DOI: 10.1186/s12967-024-05877-2] [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: 09/11/2024] [Accepted: 11/11/2024] [Indexed: 12/07/2024] Open
Abstract
Lung Cancer (LC) is characterized by chemoresistance, which poses a significant clinical challenge and results in a poor prognosis for patients. Long non-coding RNAs (lncRNAs) have recently gained recognition as crucial mediators of chemoresistance in LC. Through the regulation of key cellular processes, these molecules play important roles in the progression of LC and response to therapy. The mechanisms by which lncRNAs affect chemoresistance include the modulation of gene expression, chromatin structure, microRNA interactions, and signaling pathways. Exosomes have emerged as key mediators of lncRNA-driven chemoresistance, facilitating the transfer of resistance-associated lncRNAs between cancer cells and contributing to tumor development. Consequently, exosomal lncRNAs may serve as biomarkers and therapeutic targets for the treatment of LC. Therapeutic strategies targeting lncRNAs offer novel approaches to circumvent chemoresistance. Different approaches, including RNA interference (RNAi) and antisense oligonucleotides (ASOs), are available to degrade lncRNAs or alter their function. ASO-based therapies are effective at reducing lncRNA expression levels, increasing chemotherapy sensitivity, and improving clinical outcomes. The use of these strategies can facilitate the development of targeted interventions designed to disrupt lncRNA-mediated mechanisms of chemoresistance. An important aspect of this review is the discussion of the complex relationship between lncRNAs and drug resistance in LC, particularly through exosomal pathways, and the development of innovative therapeutic strategies to enhance drug efficacy by targeting lncRNAs. The development of new pathways and interventions for treating LC holds promise in overcoming this resistance.
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Affiliation(s)
- Ghaliah Obaid Alnefaie
- Department of Pathology, College of Medicine, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia.
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Hamdy NM, El-Sisi MG, Ibrahim SM, ElNokoudy H, Hady AA, Abd-Ellatef GEF, Sallam AAM, Barakat BM. In silico analysis and comprehensive review of circular-RNA regulatory roles in breast diseases; a step-toward non-coding RNA precision. Pathol Res Pract 2024; 263:155651. [PMID: 39454476 DOI: 10.1016/j.prp.2024.155651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024]
Abstract
In the current comprehensive review, we first highlighted circRNAs, which are key ncRNAs. Next, we discussed the relationships among circRNAs and breast cancer subtypes via in silico databases analysis and extensive literature search. CircRNAs, that sponge miRNA axes or act as silencers of oncogenic mRNAs, have been extensively addressed in the context of this review. During BC pathogenesis, the circRNA/microRNA/messenger RNA (mRNA) axis plays a major role in disease growth, progression, and survival/resistance and could be targeted for improved treatment options. This review also aimed to address oncogenic and tumor suppressor mRNAs, which are regulated by various circRNAs in BC. Moreover, we mentioned the relation of different circRNAs with cancer hallmarks, patient survival together with drug resistance. Additionally, we discussed circRNAs as vaccines and biomarkers in BC. Finally, we studied exosomal circRNAs as a hot interesting area in the research. REVIEW SIGNIFICANCE: Via using in silico databases, bioinformatics analysis, and a thorough literature search to first highlight circRNA as a crucial ncRNA and its biogenesis, and then we explored the connection between circRNA and breast illnesses. In the framework of the review, circRNA sponged-miRNAs axis or as silencers to oncogenic mRNAs were extensively discussed. In the pathophysiology of BC, the circular RNA/microRNA/messenger RNA axis is crucial for the propagation of the disease and resistance that may be targeted for more effective treatment options, in order to confront tumor suppressor and oncogenic mRNAs that are presently regulated by circRNAs in BC. For better patient results, we advised further mechanistic research to elucidate additional ncRNA axis that may be targeted for the therapy of BC and for prognosis/ or early diagnosis.
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Affiliation(s)
- Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
| | - Mona G El-Sisi
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt
| | - Sherine M Ibrahim
- Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt
| | - Heba ElNokoudy
- Medication Management & Pharmacy Affairs, Egypt Healthcare Authority, Cairo, Egypt
| | - Ahmad A Hady
- Clinical Oncology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Gamal Eldein Fathy Abd-Ellatef
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt
| | - Al-Aliaa M Sallam
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Bassant Mohamed Barakat
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al Baha University, Al Baha 1988, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11651, Egypt
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8
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Sipos F, Műzes G. Interconnection of CD133 Stem Cell Marker with Autophagy and Apoptosis in Colorectal Cancer. Int J Mol Sci 2024; 25:11201. [PMID: 39456981 PMCID: PMC11508732 DOI: 10.3390/ijms252011201] [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: 09/21/2024] [Revised: 10/09/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
CD133 protein expression is observable in differentiated cells, stem cells, and progenitor cells within normal tissues, as well as in tumor tissues, including colorectal cancer cells. The CD133 protein is the predominant cell surface marker utilized to detect cancer cells exhibiting stem cell-like characteristics. CD133 alters common abnormal processes in colorectal cancer, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin pathways. Autophagy is a cellular self-digestion mechanism that preserves the intracellular milieu and plays a dual regulatory role in cancer. In cancer cells, apoptosis is a critical cell death mechanism that can impede cancer progression. CD133 can modulate autophagy and apoptosis in colorectal cancer cells via several signaling pathways; hence, it is involved in the regulation of these intricate processes. This can be an explanation for why CD133 expression is associated with enhanced cellular self-renewal, migration, invasion, and survival under stress conditions in colorectal cancer. The purpose of this review article is to explain the complex relationship between the CD133 protein, apoptosis, and autophagy. We also want to highlight the possible ways that CD133-mediated autophagy may affect the apoptosis of colorectal cancer cells. Targeting the aforementioned mechanisms may have a significant therapeutic role in eliminating CD133-positive stem cell-phenotype colorectal cancer cells, which can be responsible for tumor recurrence.
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Affiliation(s)
- Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary
| | - Györgyi Műzes
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary
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Kovale L, Singh MK, Kim J, Ha J. Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer. Int J Mol Sci 2024; 25:8647. [PMID: 39201332 PMCID: PMC11354724 DOI: 10.3390/ijms25168647] [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: 06/11/2024] [Revised: 07/30/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.
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Affiliation(s)
- Lochana Kovale
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
| | - Joungmok Kim
- Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Joohun Ha
- Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; (L.K.); (M.K.S.)
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10
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Zhang H, Hu S, Sanches JGP, Li Y, Wei Y, Pu C, Zhang J. Sorcin promotes proliferation of hepatocellular carcinoma by regulating VEGFA/B via PI3K pathway. J Physiol Biochem 2024; 80:381-392. [PMID: 38536659 DOI: 10.1007/s13105-024-01011-4] [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: 10/06/2023] [Accepted: 02/15/2024] [Indexed: 05/07/2024]
Abstract
Hepatocellular carcinoma (HCC) is a highly vascularized tumor, one of the most common and lethal cancer-related tumor deaths worldwide, with cell proliferation playing a key role. In this study our western blot results and data from TAGC demonstrate a strong association between Sorcin (SRI) overexpression and poor outcomes in HCC. Moreover, SRI overexpression was remarkably effective in promoting proliferation in vitro and increasing tumor growth in vivo, which were attenuated by knocking down SRI. Mechanistically, SRI regulated vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor B (VEGFB) through PI3K/Akt/FOXO1 signal pathway. Overall, our study indicates that SRI stimulates HCC growth by controlling VEGFA/B, which presents a fresh insight into the pathogenesis of hepatocarcinogenesis and a new therapeutic target for HCC.
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Affiliation(s)
- Huan Zhang
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Shanshan Hu
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Jaceline Gislaine Pires Sanches
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Yizi Li
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Yuanyi Wei
- Key Laboratory of Tumor Metastasis of Liaoning Province, Dalian, 116044, China
| | - Chunwen Pu
- Dalian Public Health Clinical Center, Dalian Municipal Research Institute for Public Health, Dalian, 116031, China.
| | - Jun Zhang
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
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11
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Zaarour RF, Ribeiro M, Azzarone B, Kapoor S, Chouaib S. Tumor microenvironment-induced tumor cell plasticity: relationship with hypoxic stress and impact on tumor resistance. Front Oncol 2023; 13:1222575. [PMID: 37886168 PMCID: PMC10598765 DOI: 10.3389/fonc.2023.1222575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 09/27/2023] [Indexed: 10/28/2023] Open
Abstract
The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hypoxia functions in include its regulation of tumor heterogeneity and plasticity. While hypoxia has been reported as a major player in tumor survival and dissemination regulation, the significance of hypoxia inducible factors in cancer stem cell development remains poorly understood. Several reports indicate that the emergence of cancer stem cells in addition to their phenotype and function within a hypoxic tumor microenvironment impacts cancer progression. In this respect, evidence showed that cancer stem cells are key elements of intratumoral heterogeneity and more importantly are responsible for tumor relapse and escape to treatments. This paper briefly reviews our current knowledge of the interaction between tumor hypoxic stress and its role in stemness acquisition and maintenance. Our review extensively covers the influence of hypoxia on the formation and maintenance of cancer stem cells and discusses the potential of targeting hypoxia-induced alterations in the expression and function of the so far known stem cell markers in cancer therapy approaches. We believe that a better and integrated understanding of the effect of hypoxia on stemness during carcinogenesis might lead to new strategies for exploiting hypoxia-associated pathways and their targeting in the clinical setting in order to overcome resistance mechanisms. More importantly, at the present time, efforts are oriented towards the design of innovative therapeutical approaches that specifically target cancer stem cells.
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Affiliation(s)
- RF. Zaarour
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - M. Ribeiro
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - B. Azzarone
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - S. Kapoor
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - S. Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, Villejuif, France
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12
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Abdollahi E, Mozdarani H, Alizadeh BZ. Role of circ-FOXO3 and miR-23a in radiosensitivity of breast cancer. Breast Cancer 2023; 30:714-726. [PMID: 37222952 DOI: 10.1007/s12282-023-01463-4] [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: 11/28/2022] [Accepted: 04/25/2023] [Indexed: 05/25/2023]
Abstract
Identifying the radiosensitivity of cells before radiotherapy (RT) in breast cancer (BC) patients allows appropriate switching between routinely used treatment regimens and reduces adverse side effects in exposed patients. In this study, blood was collected from 60 women diagnosed with Invasive Ductal Carcinoma (IDC) BC and 20 healthy women. To predict cellular radiosensitivity, a standard G2-chromosomal assay was performed. From these 60 samples, 20 BC patients were found to be radiosensitive based on the G2 assay. Therefore, molecular studies were finally performed on two equal groups (20 samples each) of patients with and without cellular radiosensitivity. QPCR was performed to examine the expression levels of circ-FOXO3 and miR-23a in peripheral blood mononuclear cells (PBMCs) and RNA sensitivity and specificity were determined by plotting Receiver Operating Characteristic (ROC) curves. Binary logistic regression was performed to identify RNA involvement in BC and cellular radiosensitivity (CR) in BC patients. Meanwhile, qPCR was used to compare differential RNA expression in the radiosensitive MCF-7 and radioresistant MDA-MB-231 cell lines. An annexin -V FITC/PI binding assay was used to measure cell apoptosis 24 and 48 h after 2 Gy, 4 Gy, and 8 Gy gamma-irradiation. Results indicated that circ-FOXO3 was downregulated and miR-23a was upregulated in BC patients. RNA expression levels were directly associated with CR. Cell line results showed that circ-FOXO3 overexpression induced apoptosis in the MCF-7 cell line and miR-23a overexpression inhibited apoptosis in the MDA-MB-231 cell line. Evaluation of the ROC curves revealed that both RNAs had acceptable specificity and sensitivity in predicting CR in BC patients. Binary logistic regression showed that both RNAs were also successful in predicting breast cancer. Although only circ-FOXO3 has been shown to predict CR in BC patients, circ-FOXO3 may function as a tumor suppressor and miR-23a may function as oncomiR in BC. Circ-FOXO3 and miR-23a may be promising potential biomarkers for BC prediction. Furthermore, Circ-FOXO3 could be a potential biomarker for predicting CR in BC patients.
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Affiliation(s)
- Elahe Abdollahi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Mozdarani
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Behrooz Z Alizadeh
- Unit of Personalized Medicine, Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands
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13
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Gopikrishnan M, R HC, R G, Ashour HM, Pintus G, Hammad M, Kashyap MK, C GPD, Zayed H. Therapeutic and diagnostic applications of exosomal circRNAs in breast cancer. Funct Integr Genomics 2023; 23:184. [PMID: 37243750 PMCID: PMC10224846 DOI: 10.1007/s10142-023-01083-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 04/29/2023] [Accepted: 05/02/2023] [Indexed: 05/29/2023]
Abstract
Circular RNAs (circRNAs) are regulatory elements that are involved in orchestrating gene expression and protein functions and are implicated in various biological processes including cancer. Notably, breast cancer has a significant mortality rate and is one of the most common malignancies in women. CircRNAs have been demonstrated to contribute to the pathogenesis of breast cancer including its initiation, progression, metastasis, and resistance to drugs. By acting as miRNA sponges, circRNAs can indirectly influence gene expression by disrupting miRNA regulation of their target genes, ultimately altering the course of cancer development and progression. Additionally, circRNAs can interact with proteins and modulate their functions including signaling pathways involved in the initiation and development of cancer. Recently, circRNAs can encode peptides that play a role in the pathophysiology of breast cancer and other diseases and their potential as diagnostic biomarkers and therapeutic targets for various cancers including breast cancer. CircRNAs possess biomarkers that differentiate, such as stability, specificity, and sensitivity, and can be detected in several biological specimens such as blood, saliva, and urine. Moreover, circRNAs play an important role in various cellular processes including cell proliferation, differentiation, and apoptosis, all of which are integral factors in the development and progression of cancer. This review synthesizes the functions of circRNAs in breast cancer, scrutinizing their contributions to the onset and evolution of the disease through their interactions with exosomes and cancer-related intracellular pathways. It also delves into the potential use of circRNA as a biomarker and therapeutic target against breast cancer. It discusses various databases and online tools that offer crucial circRNA information and regulatory networks. Lastly, the challenges and prospects of utilizing circRNAs in clinical settings associated with breast cancer are explored.
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Affiliation(s)
- Mohanraj Gopikrishnan
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, 632014, Tamil Nadu, India
| | - Hephzibah Cathryn R
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, 632014, Tamil Nadu, India
| | - Gnanasambandan R
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, 632014, Tamil Nadu, India
| | - Hossam M Ashour
- Department of Integrative Biology, College of Arts and Sciences, University of South Florida, St. Petersburg, Florida, 33701, USA
| | - Gianfranco Pintus
- Department of Biomedical Sciences, University of Sassari, 07100, Sassari, Italy
| | - Mohamed Hammad
- Department of Stem Cell Biology and Regenerative Medicine, City of Hope Beckman Research Institute, Duarte, California, USA
| | - Manoj Kumar Kashyap
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Manesar (Gurugram), Panchgaon, Haryana (HR), 122413, India
- Clinical Biosamples & Research Services (CBRS), Noida, Uttar Pradesh, 201301, India
| | - George Priya Doss C
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, 632014, Tamil Nadu, India.
| | - Hatem Zayed
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, 2713, Doha, Qatar.
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14
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Wu Q, Sharma D. Autophagy and Breast Cancer: Connected in Growth, Progression, and Therapy. Cells 2023; 12:1156. [PMID: 37190065 PMCID: PMC10136604 DOI: 10.3390/cells12081156] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/29/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Despite an increase in the incidence of breast cancer worldwide, overall prognosis has been consistently improving owing to the development of multiple targeted therapies and novel combination regimens including endocrine therapies, aromatase inhibitors, Her2-targeted therapies, and cdk4/6 inhibitors. Immunotherapy is also being actively examined for some breast cancer subtypes. This overall positive outlook is marred by the development of resistance or reduced efficacy of the drug combinations, but the underlying mechanisms are somewhat unclear. It is interesting to note that cancer cells quickly adapt and evade most therapies by activating autophagy, a catabolic process designed to recycle damaged cellular components and provide energy. In this review, we discuss the role of autophagy and autophagy-associated proteins in breast cancer growth, drug sensitivity, tumor dormancy, stemness, and recurrence. We further explore how autophagy intersects and reduces the efficacy of endocrine therapies, targeted therapies, radiotherapy, chemotherapies as well as immunotherapy via modulating various intermediate proteins, miRs, and lncRNAs. Lastly, the potential application of autophagy inhibitors and bioactive molecules to improve the anticancer effects of drugs by circumventing the cytoprotective autophagy is discussed.
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Affiliation(s)
| | - Dipali Sharma
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287-0013, USA
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15
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Construction of a prognostic risk assessment model for HER2 + breast cancer based on autophagy-related genes. Breast Cancer 2023; 30:478-488. [PMID: 36856932 DOI: 10.1007/s12282-023-01440-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/15/2023] [Indexed: 03/02/2023]
Abstract
Although breast cancer (BC) has a low mortality rate relative to other cancers, it prominently affects the survival of patients with human epidermal growth factor receptor-2 (HER2 +) BC due to its high recurrence rate. By far, it has been found that autophagy can affect various tumor occurrence and development, as well as patients' prognosis. HER2 + BC patient samples and autophagy-related genes (ARGs) were acquired from a public database, least absolute shrinkage and selection operator (LASSO) and Cox analyses (including univariate and multivariate analyses) were utilized to construct a 9-ARGs model, which was verified by using HER2 + BC patient samples in The Cancer Genome Atlas (TCGA) dataset. Sample risk score was worked out based on characteristic genes, and prominent differences in overall survival were tracked down between high- and low-risk groups. Predictive ability of the model was validated by drawing receiver operating characteristic (ROC) curves and then calculating the area under the curves (AUC) value. Results showed good accuracy and prediction ability of the model in both validation set and training set. For the purpose of facilitating model application in clinical practice, we constructed a nomogram combing clinical factors and risk scores to evaluate 1-year, 3-year and 5-year survival of HER2 + BC patients. In addition, we assessed the correlation of risk score with tumor mutational burden and tumor immune infiltration. Results exhibited that in a high-risk group, tumor mutation was relatively high, while tumor immune infiltration was relatively poor. Overall, based on ARGs, the prognostic signature in this study can tellingly evaluate prognoses of HER2 + BC patients and provide a reference for clinicians.
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16
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Preclinical and Clinical Trials of New Treatment Strategies Targeting Cancer Stem Cells in Subtypes of Breast Cancer. Cells 2023; 12:cells12050720. [PMID: 36899854 PMCID: PMC10001180 DOI: 10.3390/cells12050720] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/01/2023] [Accepted: 02/09/2023] [Indexed: 02/26/2023] Open
Abstract
Breast cancer (BC) can be classified into various histological subtypes, each associated with different prognoses and treatment options, including surgery, radiation, chemotherapy, and endocrine therapy. Despite advances in this area, many patients still face treatment failure, the risk of metastasis, and disease recurrence, which can ultimately lead to death. Mammary tumors, like other solid tumors, contain a population of small cells known as cancer stem-like cells (CSCs) that have high tumorigenic potential and are involved in cancer initiation, progression, metastasis, tumor recurrence, and resistance to therapy. Therefore, designing therapies specifically targeting at CSCs could help to control the growth of this cell population, leading to increased survival rates for BC patients. In this review, we discuss the characteristics of CSCs, their surface biomarkers, and the active signaling pathways associated with the acquisition of stemness in BC. We also cover preclinical and clinical studies that focus on evaluating new therapy systems targeted at CSCs in BC through various combinations of treatments, targeted delivery systems, and potential new drugs that inhibit the properties that allow these cells to survive and proliferate.
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17
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Mallet JF, Shahbazi R, Alsadi N, Saleem A, Sobiesiak A, Arnason JT, Matar C. Role of a Mixture of Polyphenol Compounds Released after Blueberry Fermentation in Chemoprevention of Mammary Carcinoma: In Vivo Involvement of miR-145. Int J Mol Sci 2023; 24:ijms24043677. [PMID: 36835085 PMCID: PMC9966222 DOI: 10.3390/ijms24043677] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/29/2023] [Accepted: 01/30/2023] [Indexed: 02/17/2023] Open
Abstract
Epigenetic mechanisms such as microRNA (miRNA) deregulation seem to exert a central role in breast cancer initiation and progression. Therefore, targeting epigenetics deregulation may be an effective strategy for preventing and halting carcinogenesis. Studies have revealed the significant role of naturally occurring polyphenolic compounds derived from fermented blueberry fruits in cancer chemoprevention by modulation of cancer stem cell development through the epigenetic mechanism and regulation of cellular signaling pathways. In this study, we first investigated the phytochemical changes during the blueberry fermentation process. Fermentation favored the release of oligomers and bioactive compounds such as protocatechuic acid (PCA), gallic acid, and catechol. Next, we investigated the chemopreventive potentials of a polyphenolic mixture containing PCA, gallic acid, and catechin found in fermented blueberry juice in a breast cancer model by measuring miRNA expression and the signaling pathways involved in breast cancer stemness and invasion. To this end, 4T1 and MDA-MB-231 cell lines were treated with different doses of the polyphenolic mixture for 24 h. Additionally, female Balb/c mice were fed with this mixture for five weeks; two weeks before and three weeks after receiving 4T1 cells. Mammosphere formation was assayed in both cell lines and the single-cell suspension obtained from the tumor. Lung metastases were counted by isolating 6-thioguanine-resistant cells present in the lungs. In addition, we conducted RT-qPCR and Western blot analysis to validate the expression of targeted miRNAs and proteins, respectively. We found a significant reduction in mammosphere formation in both cell lines treated with the mixture and in tumoral primary cells isolated from mice treated with the polyphenolic compound. The number of colony-forming units of 4T1 cells in the lungs was significantly lower in the treatment group compared to the control group. miR-145 expression significantly increased in the tumor samples of mice treated with the polyphenolic mixture compared to the control group. Furthermore, a significant increase in FOXO1 levels was noted in both cell lines treated with the mixture. Overall, our results show that phenolic compounds found in fermented blueberry delay the formation of tumor-initiating cells in vitro and in vivo and reduce the spread of metastatic cells. The protective mechanisms seem to be related, at least partly, to the epigenetic modulation of mir-145 and its signaling pathways.
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Affiliation(s)
- Jean-François Mallet
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Roghayeh Shahbazi
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Nawal Alsadi
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Ammar Saleem
- Laboratory for the Analysis of Natural and Synthetic Environmental Toxins, Department of Biology, University of Ottawa, 30 Marie Curie Private, Ottawa, ON K1N 6N5, Canada
| | - Agnes Sobiesiak
- Laboratory for the Analysis of Natural and Synthetic Environmental Toxins, Department of Biology, University of Ottawa, 30 Marie Curie Private, Ottawa, ON K1N 6N5, Canada
| | - John Thor Arnason
- Laboratory for the Analysis of Natural and Synthetic Environmental Toxins, Department of Biology, University of Ottawa, 30 Marie Curie Private, Ottawa, ON K1N 6N5, Canada
| | - Chantal Matar
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Correspondence: ; Tel.: +613-562-5800 (ext. 8322)
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18
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Zhang L, Chen W, Liu S, Chen C. Targeting Breast Cancer Stem Cells. Int J Biol Sci 2023; 19:552-570. [PMID: 36632469 PMCID: PMC9830502 DOI: 10.7150/ijbs.76187] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 12/09/2022] [Indexed: 01/04/2023] Open
Abstract
The potential roles of breast cancer stem cells (BCSCs) in tumor initiation and recurrence have been recognized for many decades. Due to their strong capacity for self-renewal and differentiation, BCSCs are the major reasons for poor clinical outcomes and low therapeutic response. Several hypotheses on the origin of cancer stem cells have been proposed, including critical gene mutations in stem cells, dedifferentiation of somatic cells, and cell plasticity remodeling by epithelial-mesenchymal transition (EMT) and the tumor microenvironment. Moreover, the tumor microenvironment, including cellular components and cytokines, modulates the self-renewal and therapeutic resistance of BCSCs. Small molecules, antibodies, and chimeric antigen receptor (CAR)-T cells targeting BCSCs have been developed, and their applications in combination with conventional therapies are undergoing clinical trials. In this review, we focus on the features of BCSCs, emphasize the major factors and tumor environment that regulate the stemness of BCSCs, and discuss potential BCSC-targeting therapies.
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Affiliation(s)
- Lu Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai paracrine Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai 200032, China
| | - Wenmin Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming 650201, China.,Kunming College of Life Sciences, the University of the Chinese Academy of Sciences, Kunming 650201, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai paracrine Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai 200032, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.,✉ Corresponding authors: Ceshi Chen, E-mail: or Suling Liu, E-mail:
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming 650201, China.,Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China.,The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China.,✉ Corresponding authors: Ceshi Chen, E-mail: or Suling Liu, E-mail:
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19
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Ervin EH, French R, Chang CH, Pauklin S. Inside the stemness engine: Mechanistic links between deregulated transcription factors and stemness in cancer. Semin Cancer Biol 2022; 87:48-83. [PMID: 36347438 DOI: 10.1016/j.semcancer.2022.11.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/22/2022] [Accepted: 11/03/2022] [Indexed: 11/07/2022]
Abstract
Cell identity is largely determined by its transcriptional profile. In tumour, deregulation of transcription factor expression and/or activity enables cancer cell to acquire a stem-like state characterised by capacity to self-renew, differentiate and form tumours in vivo. These stem-like cancer cells are highly metastatic and therapy resistant, thus warranting a more complete understanding of the molecular mechanisms downstream of the transcription factors that mediate the establishment of stemness state. Here, we review recent research findings that provide a mechanistic link between the commonly deregulated transcription factors and stemness in cancer. In particular, we describe the role of master transcription factors (SOX, OCT4, NANOG, KLF, BRACHYURY, SALL, HOX, FOX and RUNX), signalling-regulated transcription factors (SMAD, β-catenin, YAP, TAZ, AP-1, NOTCH, STAT, GLI, ETS and NF-κB) and unclassified transcription factors (c-MYC, HIF, EMT transcription factors and P53) across diverse tumour types, thereby yielding a comprehensive overview identifying shared downstream targets, highlighting unique mechanisms and discussing complexities.
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Affiliation(s)
- Egle-Helene Ervin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Rhiannon French
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Chao-Hui Chang
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
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20
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Kandil NS, Kandil LS, Mohamed R, Selima M, El Nemr M, Barakat AR, Alwany YN. The Role of miRNA-182 and FOXO3 Expression in Breast Cancer. Asian Pac J Cancer Prev 2022; 23:3361-3370. [PMID: 36308360 PMCID: PMC9924337 DOI: 10.31557/apjcp.2022.23.10.3361] [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: 03/17/2022] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE evaluating the role of FOXO3 mRNA and mi RNA 182-5P expression levels in BC patients. METHOD 25 Samples of breast cancer and paired samples of non-cancerous tissues from the same resected breast were obtained from 25 female patients suffering from breast cancer and examined and analyzed by real time PCR to detect the expression levels of FOXO3 mRNA and mi RNA 182-5P. Patients' data were collected from patients medical records. RESULTS Foxo3 m RNA expression was down regulated in BC tissues (1.37± 1.96) as compared to control group (23.62 ± 54.39) and decreased FOXO3 expression was associated with larger tumor size (p= 0.046), late histopathological grading (p= 0.002), late TNM staging (<0.001) and increased miR-182 expression (p= 0.025). We found that expression level of miR-182 was significantly higher among breast cancer group (1.10±1.15) as compared to the control group (0.58±0.96 ) with p value = 0.017. We noted a significant increased expression associated with larger tumor size (p= 0.002), late histopathological grading (p= 0.008), late TNM staging (p= 0.002) and decreased FOXO3 expression (p= 0.025). A significant negative correlation between miR-182 and FOXO3 mRNA fold expression with r = - 0.447, and a p value of 0.025, this could be attributed to miRNA targeting FOXO gene. COCLUSION Down regulation of FOXO3 and up regulation of miR-182 expression was associated with advanced breast cancer. The negative correlation between miR-182 and FOXO3 mRNA could be attributed to miRNA targeting FOXO gene.
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Affiliation(s)
- Noha S Kandil
- Department of Chemical Pathology, Medical Research Institute, Alexandria University, Egypt. ,For Correspondence:
| | - Lamia Said Kandil
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University, Egypt. ,Lecturer in the School of Biological Sciences, Faculty of Science, University of East Anglia, UK.
| | - Radwa Mohamed
- Department of Pathology, Medical Research Institute, Alexandria University, Egypt.
| | - Mohamed Selima
- Department of Surgery, Medical Research Institute, Alexandria University, Egypt.
| | - Mohamed El Nemr
- Department of Cancer Management and Research, Medical Research Institute, Alexandria University, Alexandria, Egypt. ,Centre hospitalier de Troyes, radiotherapy department, France.
| | | | - Yasmine Nagy Alwany
- Department of Cancer Management and Research, Medical Research Institute, Alexandria University, Alexandria, Egypt.
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Akhtar S, Hourani S, Therachiyil L, Al-Dhfyan A, Agouni A, Zeidan A, Uddin S, Korashy HM. Epigenetic Regulation of Cancer Stem Cells by the Aryl Hydrocarbon Receptor Pathway. Semin Cancer Biol 2022; 83:177-196. [PMID: 32877761 DOI: 10.1016/j.semcancer.2020.08.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/20/2020] [Accepted: 08/23/2020] [Indexed: 12/14/2022]
Abstract
Compelling evidence has demonstrated that tumor bulk comprises distinctive subset of cells generally referred as cancer stem cells (CSCs) that have been proposed as a strong sustainer and promoter of tumorigenesis and therapeutic resistance. These distinguished properties of CSCs have raised interest in understanding the molecular mechanisms that govern the maintenance of these cells. Numerous experimental and epidemiological studies have demonstrated that exposure to environmental toxins such as the polycyclic aromatic hydrocarbons (PAHs) is strongly involved in cancer initiation and progression. The PAH-induced carcinogenesis is shown to be mediated through the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR)/Cytochrome P4501A pathway, suggesting a possible direct link between AhR and CSCs. Several recent studies have investigated the role of AhR in CSCs self-renewal and maintenance, however the molecular mechanisms and particularly the epigenetic regulations of CSCs by the AhR/CYP1A pathway have not been reviewed before. In this review, we first summarize the crosstalk between AhR and cancer genetics, with a particular emphasis on the mechanisms relevant to CSCs such as Wnt/β-catenin, Notch, NF-κB, and PTEN-PI3K/Akt signaling pathways. The second part of this review discusses the recent advances and studies highlighting the epigenetic mechanisms mediated by the AhR/CYP1A pathway that control CSC gene expression, self-renewal, and chemoresistance in various human cancers. Furthermore, the review also sheds light on the importance of targeting the epigenetic pathways as a novel therapeutic approach against CSCs.
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Affiliation(s)
- Sabah Akhtar
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Shireen Hourani
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Lubna Therachiyil
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Abdullah Al-Dhfyan
- Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
| | - Abdelali Agouni
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Asad Zeidan
- Department of Biomedical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Hesham M Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
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22
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ANGPTL1 attenuates cancer migration, invasion, and stemness through regulating FOXO3a-mediated SOX2 expression in colorectal cancer. Clin Sci (Lond) 2022; 136:657-673. [PMID: 35475476 PMCID: PMC9093149 DOI: 10.1042/cs20220043] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 12/16/2022]
Abstract
Angiopoietin-like protein 1 (ANGPTL1) is a member of the ANGPTL family that suppresses angiogenesis, cancer invasion, metastasis, and cancer progression. ANGPTL1 is down-regulated in various cancers including colorectal cancer (CRC); however, the effects and mechanisms of ANGPTL1 on liver metastasis and cancer stemness in CRC are poorly understood. In the present study, we identified that ANGPTL1 was down-regulated in CRC and inversely correlated with metastasis and poor clinical outcomes in CRC patients form the ONCOMINE database and Human Tissue Microarray staining. ANGPTL1 significantly suppressed the migration/invasion abilities, the expression of cancer stem cell (CSC) markers, and sphere formation by enhancing FOXO3a expression, which contributed to the reduction of stem cell transcription factor SOX2 expression in CRC cells. Consistently, overexpression of ANGPTL1 reduced liver metastasis, tumor growth, and tumorigenicity in tumor-bearing mice. ANGPTL1 expression was negatively correlated with CSC markers expression and poor clinical outcomes in CRC patients. Taken together, these findings demonstrate that the molecular mechanisms of ANGPTL1 in colorectal cancer stem cell progression may provide a novel therapeutic strategy for CRC.
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23
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The Discovery of New Drug-Target Interactions for Breast Cancer Treatment. Molecules 2021; 26:molecules26247474. [PMID: 34946556 PMCID: PMC8704452 DOI: 10.3390/molecules26247474] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 01/09/2023] Open
Abstract
Drug–target interaction (DTIs) prediction plays a vital role in probing new targets for breast cancer research. Considering the multifaceted challenges associated with experimental methods identifying DTIs, the in silico prediction of such interactions merits exploration. In this study, we develop a feature-based method to infer unknown DTIs, called PsePDC-DTIs, which fuses information regarding protein sequences extracted by pseudo-position specific scoring matrix (PsePSSM), detrended cross-correlation analysis coefficient (DCCA coefficient), and an FP2 format molecular fingerprint descriptor of drug compounds. In addition, the synthetic minority oversampling technique (SMOTE) is employed for dealing with the imbalanced data after Lasso dimensionality reduction. Then, the processed feature vectors are put into a random forest classifier to perform DTIs predictions on four gold standard datasets, including nuclear receptors (NR), G-protein-coupled receptors (GPCR), ion channels (IC), and enzymes (E). Furthermore, we explore new targets for breast cancer treatment using its risk genes identified from large-scale genome-wide genetic studies using PsePDC-DTIs. Through five-fold cross-validation, the average values of accuracy in NR, GPCR, IC, and E datasets are 95.28%, 96.19%, 96.74%, and 98.22%, respectively. The PsePDC-DTIs model provides us with 10 potential DTIs for breast cancer treatment, among which erlotinib (DB00530) and FGFR2 (hsa2263), caffeine (DB00201) and KCNN4 (hsa3783), as well as afatinib (DB08916) and FGFR2 (hsa2263) are found with direct or inferred evidence. The PsePDC-DTIs model has achieved good prediction results, establishing the validity and superiority of the proposed method.
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24
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Scioli MG, Terriaca S, Fiorelli E, Storti G, Fabbri G, Cervelli V, Orlandi A. Extracellular Vesicles and Cancer Stem Cells in Tumor Progression: New Therapeutic Perspectives. Int J Mol Sci 2021; 22:10572. [PMID: 34638913 PMCID: PMC8508599 DOI: 10.3390/ijms221910572] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/27/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor progression, drug resistance, and disease relapse. Furthermore, CSCs secrete a wide variety of extracellular vesicles (EVs) with different cargos, including proteins, lipids, ssDNA, dsDNA, mRNA, siRNA, or miRNA. EVs are internalized by other cells, orienting the microenvironment toward a protumorigenic and prometastatic one. Given their importance in tumor growth and metastasis, EVs could be exploited as a new therapeutic target. The inhibition of biogenesis, release, or uptake of EVs could represent an efficacious strategy to impair the cross-talk between CSCs and other cells present in the tumor microenvironment. Moreover, natural or synthetic EVs could represent suitable carriers for drugs or bioactive molecules to target specific cell populations, including CSCs. This review will discuss the role of CSCs and EVs in tumor growth, progression, and metastasis and how they affect drug resistance and disease relapse. Furthermore, we will analyze the potential role of EVs as a target or vehicle of new therapies.
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Affiliation(s)
- Maria Giovanna Scioli
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
| | - Sonia Terriaca
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
| | - Elena Fiorelli
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
| | - Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Roma, Italy; (G.S.); (V.C.)
| | - Giulia Fabbri
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Roma, Italy; (G.S.); (V.C.)
| | - Augusto Orlandi
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
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25
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Polyphenol-Enriched Blueberry Preparation Controls Breast Cancer Stem Cells by Targeting FOXO1 and miR-145. Molecules 2021; 26:molecules26144330. [PMID: 34299605 PMCID: PMC8304479 DOI: 10.3390/molecules26144330] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/12/2021] [Accepted: 07/12/2021] [Indexed: 12/15/2022] Open
Abstract
Scientific evidence supports the early deregulation of epigenetic profiles during breast carcinogenesis. Research shows that cellular transformation, carcinogenesis, and stemness maintenance are regulated by epigenetic-specific changes that involve microRNAs (miRNAs). Dietary bioactive compounds such as blueberry polyphenols may modulate susceptibility to breast cancer by the modulation of CSC survival and self-renewal pathways through the epigenetic mechanism, including the regulation of miRNA expression. Therefore, the current study aimed to assay the effect of polyphenol enriched blueberry preparation (PEBP) or non-fermented blueberry juice (NBJ) on the modulation of miRNA signature and the target proteins associated with different clinical-pathological characteristics of breast cancer such as stemness, invasion, and chemoresistance using breast cancer cell lines. To this end, 4T1 and MB-MDM-231 cell lines were exposed to NBJ or PEBP for 24 h. miRNA profiling was performed in breast cancer cell cultures, and RT-qPCR was undertaken to assay the expression of target miRNA. The expression of target proteins was examined by Western blotting. Profiling of miRNA revealed that several miRNAs associated with different clinical-pathological characteristics were differentially expressed in cells treated with PEBP. The validation study showed significant downregulation of oncogenic miR-210 expression in both 4T1 and MDA-MB-231 cells exposed to PEBP. In addition, expression of tumor suppressor miR-145 was significantly increased in both cell lines treated with PEBP. Western blot analysis showed a significant increase in the relative expression of FOXO1 in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Furthermore, a significant decrease was observed in the relative expression of N-RAS in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Our data indicate a potential chemoprevention role of PEBP through the modulation of miRNA expression, particularly miR-210 and miR-145, and protection against breast cancer development and progression. Thus, PEBP may represent a source for novel chemopreventative agents against breast cancer.
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26
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Niklaus NJ, Tokarchuk I, Zbinden M, Schläfli AM, Maycotte P, Tschan MP. The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment. Cells 2021; 10:cells10061447. [PMID: 34207792 PMCID: PMC8229352 DOI: 10.3390/cells10061447] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/04/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022] Open
Abstract
Macroautophagy (herein referred to as autophagy) is a complex catabolic process characterized by the formation of double-membrane vesicles called autophagosomes. During this process, autophagosomes engulf and deliver their intracellular content to lysosomes, where they are degraded by hydrolytic enzymes. Thereby, autophagy provides energy and building blocks to maintain cellular homeostasis and represents a dynamic recycling mechanism. Importantly, the clearance of damaged organelles and aggregated molecules by autophagy in normal cells contributes to cancer prevention. Therefore, the dysfunction of autophagy has a major impact on the cell fate and can contribute to tumorigenesis. Breast cancer is the most common cancer in women and has the highest mortality rate among all cancers in women worldwide. Breast cancer patients often have a good short-term prognosis, but long-term survivors often experience aggressive recurrence. This phenomenon might be explained by the high heterogeneity of breast cancer tumors rendering mammary tumors difficult to target. This review focuses on the mechanisms of autophagy during breast carcinogenesis and sheds light on the role of autophagy in the traits of aggressive breast cancer cells such as migration, invasion, and therapeutic resistance.
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Affiliation(s)
- Nicolas J. Niklaus
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
| | - Igor Tokarchuk
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
| | - Mara Zbinden
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
| | - Anna M. Schläfli
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
| | - Paola Maycotte
- Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Puebla 74360, Mexico;
| | - Mario P. Tschan
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
- Correspondence: ; Tel.: +41-31-632-87-80
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27
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Hegde M, Joshi MB. Comprehensive analysis of regulation of DNA methyltransferase isoforms in human breast tumors. J Cancer Res Clin Oncol 2021; 147:937-971. [PMID: 33604794 PMCID: PMC7954751 DOI: 10.1007/s00432-021-03519-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/10/2021] [Indexed: 12/14/2022]
Abstract
Significant reprogramming of epigenome is widely described during pathogenesis of breast cancer. Transformation of normal cell to hyperplastic cell and to neoplastic phenotype is associated with aberrant DNA (de)methylation, which, through promoter and enhancer methylation changes, activates oncogenes and silence tumor suppressor genes in variety of tumors including breast. DNA methylation, one of the major epigenetic mechanisms is catalyzed by evolutionarily conserved isoforms namely, DNMT1, DNMT3A and DNMT3B in humans. Over the years, studies have demonstrated intricate and complex regulation of DNMT isoforms at transcriptional, translational and post-translational levels. The recent findings of allosteric regulation of DNMT isoforms and regulation by other interacting chromatin modifying proteins emphasizes functional integrity and their contribution for the development of breast cancer and progression. DNMT isoforms are regulated by several intrinsic and extrinsic parameters. In the present review, we have extensively performed bioinformatics analysis of expression of DNMT isoforms along with their transcriptional and post-transcriptional regulators such as transcription factors, interacting proteins, hormones, cytokines and dietary elements along with their significance during pathogenesis of breast tumors. Our review manuscript provides a comprehensive understanding of key factors regulating DNMT isoforms in breast tumor pathology and documents unsolved issues.
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Affiliation(s)
- Mangala Hegde
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Planetarium Complex, Manipal, 576104, India
| | - Manjunath B Joshi
- Manipal School of Life Sciences, Manipal Academy of Higher Education, Planetarium Complex, Manipal, 576104, India.
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28
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Chmurska A, Matczak K, Marczak A. Two Faces of Autophagy in the Struggle against Cancer. Int J Mol Sci 2021; 22:2981. [PMID: 33804163 PMCID: PMC8000091 DOI: 10.3390/ijms22062981] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/10/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called "autophagy paradox", and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell's energy needs, and that the over-programmed activity of this process can lead to cell death through apoptosis. The fight against cancer is a difficult process due to high levels of resistance to chemotherapy and radiotherapy. More and more research is indicating that autophagy may play a very important role in the development of resistance by protecting cancer cells, which is why autophagy in cancer therapy can act as a "double-edged sword". This paper attempts to analyse the influence of autophagy and cancer stem cells on tumour development, and to compare new therapeutic strategies based on the modulation of these processes.
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Affiliation(s)
- Anna Chmurska
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
| | - Karolina Matczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland; (K.M.); (A.M.)
| | - Agnieszka Marczak
- Department of Medical Biophysics, Faculty of Biology and Environmental Protection, Institute of Biophysics, University of Lodz, Pomorska Street 141/143, 90-236 Lodz, Poland; (K.M.); (A.M.)
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29
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Castelli V, Giordano A, Benedetti E, Giansanti F, Quintiliani M, Cimini A, d’Angelo M. The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death. Cancers (Basel) 2021; 13:328. [PMID: 33477367 PMCID: PMC7830655 DOI: 10.3390/cancers13020328] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer is one of the primary causes of death worldwide. Tumour malignancy is related to tumor heterogeneity, which has been suggested to be due to a small subpopulation of tumor cells named cancer stem cells (CSCs). CSCs exert a key role in metastasis development, tumor recurrence, and also epithelial-mesenchymal transition, apoptotic resistance, self-renewal, tumorigenesis, differentiation, and drug resistance. Several current therapies fail to eradicate tumors due to the ability of CSCs to escape different programmed cell deaths. Thus, developing CSC-selective and programmed death-inducing therapeutic approaches appears to be of primary importance. In this review, we discuss the main programmed cell death occurring in cancer and the promising CSC-targeting agents developed in recent years. Even if the reported studies are encouraging, further investigations are necessary to establish a combination of agents able to eradicate CSCs or inhibit their growth and proliferation.
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Affiliation(s)
- Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Antonio Giordano
- Department of Medical Biotechnology, University of Siena, 53100 Siena, Italy;
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Francesco Giansanti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Massimiliano Quintiliani
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Michele d’Angelo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (E.B.); (F.G.); (M.Q.)
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30
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Farhan M, Silva M, Li S, Yan F, Fang J, Peng T, Hu J, Tsao M, Little P, Zheng W. The role of FOXOs and autophagy in cancer and metastasis-Implications in therapeutic development. Med Res Rev 2020; 40:2089-2113. [PMID: 32474970 PMCID: PMC7586888 DOI: 10.1002/med.21695] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 04/21/2020] [Accepted: 05/16/2020] [Indexed: 12/17/2022]
Abstract
Autophagy is a highly conserved intracellular degradation process that plays a crucial role in cell survival and stress reactions as well as in cancer development and metastasis. Autophagy process involves several steps including sequestration, fusion of autophagosomes with lysosomes and degradation. Forkhead box O (FOXO) transcription factors regulate the expression of genes involved in cellular metabolic activity and signaling pathways of cancer growth and metastasis. Recent evidence suggests that FOXO proteins are also involved in autophagy regulation. The relationship among FOXOs, autophagy, and cancer has been drawing attention of many who work in the field. This study summarizes the role of FOXO proteins and autophagy in cancer growth and metastasis and analyzes their potential roles in cancer disease management.
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Affiliation(s)
- Mohd Farhan
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Marta Silva
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Shuai Li
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Fengxia Yan
- Department of MedicineJinan UniversityGuangzhouChina
| | - Jiankang Fang
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Tangming Peng
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Jim Hu
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Ming‐Sound Tsao
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Peter Little
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of QueenslandWoolloongabbaQueenslandAustralia
| | - Wenhua Zheng
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
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31
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Radiotherapy-Resistant Breast Cancer Cells Enhance Tumor Progression by Enhancing Premetastatic Niche Formation through the HIF-1α-LOX Axis. Int J Mol Sci 2020; 21:ijms21218027. [PMID: 33126606 PMCID: PMC7663097 DOI: 10.3390/ijms21218027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/26/2020] [Accepted: 10/27/2020] [Indexed: 01/05/2023] Open
Abstract
Cancer stem cells (CSCs) exist in solid tumors and contribute to therapeutic resistance and disease recurrence. Previously, we reported that radiotherapy-resistant (RT-R)-MDA-MB-231 cells from highly metastatic MDA-MB-231 cells produced more CSCs than any other RT-R-breast cancer cells and showed therapeutic resistance and enhanced invasiveness. Hypoxia inducible factor-1α (HIF-1α) induced in the tumor microenvironment leads to the release of lysyl oxidase (LOX), which mediates collagen crosslinking at distant sites to facilitate environmental changes that allow cancer cells to easily metastasize. Therefore, in this study, we investigated whether RT-R-MDA-MB-231 cells induce greater HIF-1α expression, LOX secretion, and premetastatic niche formation than MDA-MB-231 cells do. RT-R-MDA-MB-231 cells increased HIF-1α expression and LOX secretion compared with MDA-MB-231 cells. Mice harboring RT-R-MDA-MB-231 cell xenografts showed enhanced tumor growth and higher expression of the CSC markers, CD44, Notch-4, and Oct3/4. In addition, mice injected with RT-R-MDA-MB-231 cells exhibited a higher level of HIF-1α in tumor tissue, increased secretion of LOX in plasma, higher induced levels of crosslinked collagen, and a higher population of CD11b+ BMDC recruitment around lung tissue, compared with those injected with MDA-MB-231 cells. These results suggest that RT-R-MDA-MB-231 cells contribute to tumor progression by enhancing premetastatic niche formation through the HIF-1α-LOX axis.
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32
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Bacillomycin D-C16 triggers apoptosis of gastric cancer cells through the PI3K/Akt and FoxO3a signaling pathways. Anticancer Drugs 2020; 30:46-55. [PMID: 30169424 DOI: 10.1097/cad.0000000000000688] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Bacillomycin D can inhibit the growth of Aspergillus ochraceus in food samples. In addition, it can induce apoptosis in and inhibit the proliferation of cancer cells, although the details of this mechanism are unknown. In this study, we separated bacillomycin D-C14, D-C15, D-C16 monomers from the Bacillus subtilis strain fmbJ. The bacillomycin D monomers containing longer fatty acid chains better induced apoptosis in Bgc-823, Sgc-7901, and Hgc-27 gastric cancer cells. The Bgc-823 cell line was the most sensitive. Acridine orange-ethidium bromide staining indicated that bacillomycin D-C16-induced Bgc-823 cell death by triggering apoptosis, characterized by membrane blebbing, cellular shrinkage, and DNA fragmentation. Flow cytometric analysis showed a bacillomycin D-C16 dose-dependent trigger of Bgc-823 apoptosis. Bacillomycin D-C16-induced the mitochondrial pathway, as indicated by a reduced Bcl-2/Bax expression ratio, enhanced cytochrome C release, and higher levels of cleaved caspase-3. Furthermore, bacillomycin D-C16 effectively repressed phosphorylation of the serine-threonine protein kinase Akt at Ser-473 and increased the levels of the FoxO3a protein. The combination of the PI3K/Akt-inhibitor BEZ235 with bacillomycin D-C16 enhanced the apoptosis of Bgc-823 cells. Together, these findings indicated that bacillomycin D-C16 induces apoptosis through the PI3K/Akt and FoxO3a signaling pathways.
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Mandhair HK, Arambasic M, Novak U, Radpour R. Molecular modulation of autophagy: New venture to target resistant cancer stem cells. World J Stem Cells 2020; 12:303-322. [PMID: 32547680 PMCID: PMC7280868 DOI: 10.4252/wjsc.v12.i5.303] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/19/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a highly regulated catabolic process in which superfluous, damaged organelles and other cytoplasmic constituents are delivered to the lysosome for clearance and the generation of macromolecule substrates during basal or stressed conditions. Autophagy is a bimodal process with a context dependent role in the initiation and the development of cancers. For instance, autophagy provides an adaptive response to cancer stem cells to survive metabolic stresses, by influencing disease propagation via modulation of essential signaling pathways or by promoting resistance to chemotherapeutics. Autophagy has been implicated in a cross talk with apoptosis. Understanding the complex interactions provides an opportunity to improve cancer therapy and the clinical outcome for the cancer patients. In this review, we provide a comprehensive view on the current knowledge on autophagy and its role in cancer cells with a particular focus on cancer stem cell homeostasis.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Miroslav Arambasic
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland.
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Rahman MA, Saha SK, Rahman MS, Uddin MJ, Uddin MS, Pang MG, Rhim H, Cho SG. Molecular Insights Into Therapeutic Potential of Autophagy Modulation by Natural Products for Cancer Stem Cells. Front Cell Dev Biol 2020; 8:283. [PMID: 32391363 PMCID: PMC7193248 DOI: 10.3389/fcell.2020.00283] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/02/2020] [Indexed: 12/24/2022] Open
Abstract
Autophagy, a cellular self-digestion process that is activated in response to stress, has a functional role in tumor formation and progression. Cancer stem cells (CSCs) accounting for a minor proportion of total cancer cells-have distinct self-renewal and differentiation abilities and promote metastasis. Researchers have shown that a numeral number of natural products using traditional experimental methods have been revealed to target CSCs. However, the specific role of autophagy with respect to CSCs and tumorigenesis using natural products are still unknown. Currently, CSCs are considered to be one of the causative reasons underlying the failure of anticancer treatment as a result of tumor recurrence, metastasis, and chemo- or radio-resistance. Autophagy may play a dual role in CSC-related resistance to anticancer treatment; it is responsible for cell fate determination and the targeted degradation of transcription factors via growth arrest. It has been established that autophagy promotes drug resistance, dormancy, and stemness and maintenance of CSCs. Surprisingly, numerous studies have also suggested that autophagy can facilitate the loss of stemness in CSCs. Here, we review current progress in research related to the multifaceted connections between autophagy modulation and CSCs control using natural products. Overall, we emphasize the importance of understanding the role of autophagy in the maintenance of different CSCs and implications of this connection for the development of new strategies for cancer treatment targeting natural products.
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Affiliation(s)
- Md Ataur Rahman
- Center for Neuroscience, Korea Institute of Science and Technology, Seoul, South Korea.,Department of Biotechnology and Genetic Engineering, Global Biotechnology & Biomedical Research Network, Islamic University, Kushtia, Bangladesh
| | - Subbroto Kumar Saha
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, South Korea.,Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Md Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, South Korea
| | - Md Jamal Uddin
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.,ABEx Bio-Research Center, Dhaka, Bangladesh
| | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.,Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, South Korea
| | - Hyewhon Rhim
- Center for Neuroscience, Korea Institute of Science and Technology, Seoul, South Korea.,Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, South Korea
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El Abbass KA, Abdellateif MS, Gawish AM, Zekri ARN, Malash I, Bahnassy AA. The Role of Breast Cancer Stem Cells and Some Related Molecular Biomarkers in Metastatic and Nonmetastatic Breast Cancer. Clin Breast Cancer 2020; 20:e373-e384. [PMID: 32299754 DOI: 10.1016/j.clbc.2019.11.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 11/24/2019] [Accepted: 11/25/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND Breast cancer stem cells (BCSCs) play important role(s) in the development and progression of invasive duct carcinoma (IDC). We assessed the role of BCSC marker expression and the number of mammospheres in cultures of breast cancer (BC) tissues and correlated these data to relevant clinicopathologic features of the patients and overall survival (OS). METHODS Fresh tumor tissue samples were collected from 44 Egyptian female patients with IDC of the breast and 25 healthy women undergoing reduction mammoplasty as a control. The mammosphere number and the RNA expression levels of some cancer stem cell-related genes (PTEN, PI3K, AKT, Wnt, and β-catenin) were assessed by reverse-transcriptase polymerase chain reaction at different stages of BCSC differentiation compared with control samples. RESULTS The number of CD44+CD24-/low cells associated significantly at the end of culture with the expression level of Wnt, β-catenin, and distant metastasis (P < .001, P = .015 and P = .003, respectively). There was significant association between the mammosphere number and CD44+CD24-/low cells as well as AKT expression (P = .040 and .021, respectively). PTEN messenger RNA expressed significantly in BC (P < .05). Wnt-RNA expression associated significantly with high tumor stage, positive lymph node status, Her2-neu overexpression, and metastasis (P = .009, .012, .026, and .001, respectively), whereas OS associated significantly with distant metastasis, Wnt, and PTEN expressions (P < .001, P = .001, P = .014, respectively). CONCLUSION BCSCs and their related genes (PTEN, PI3K, AKT, Wnt, and β-catenin) play important roles in the development and progression of BC and they can be used as potential prognostic and predictive biomarkers for patients with BC or as target therapy.
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Affiliation(s)
- Khlood Abu El Abbass
- Cell Biology and Histology, Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Azza M Gawish
- Cell Biology and Histology, Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Abdel-Rahman N Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Ibrahim Malash
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Abeer A Bahnassy
- Tissue Culture and Cytogenetics Unit, Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
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FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. Br J Cancer 2019; 122:361-371. [PMID: 31772325 PMCID: PMC7000737 DOI: 10.1038/s41416-019-0649-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 10/29/2019] [Indexed: 12/11/2022] Open
Abstract
Background ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. Methods In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). Results ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. Conclusion FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.
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37
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Prognostic Potential of Alternative Splicing Markers in Endometrial Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 18:1039-1048. [PMID: 31785579 PMCID: PMC6889075 DOI: 10.1016/j.omtn.2019.10.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 10/09/2019] [Accepted: 10/25/2019] [Indexed: 02/06/2023]
Abstract
Alternative splicing (AS), an important post-transcriptional regulatory mechanism that regulates the translation of mRNA isoforms and generates protein diversity, has been widely demonstrated to be associated with oncogenic processes. In this study, we systematically analyzed genome-wide AS patterns to explore the prognostic implications of AS in endometrial cancer (EC). A total of 2,324 AS events were identified as being associated with the overall survival of EC patients, and eleven of these events were further selected using a random forest algorithm. With the implementation of a generalized, boosted regression model, a prognostic AS model that aggregated these eleven markers was ultimately established with high performance for risk stratification in EC patients. Functional analysis of these eleven AS markers revealed various potential signaling pathways implicated in the progression of EC. Splicing network analysis demonstrated the notable correlation between the expression of splicing factors and AS markers in EC and further determined eight candidate splicing factors that could be therapeutic targets for EC. Taken together, the results of this study present the utility of AS profiling in identifying biomarkers for the prognosis of EC and provide comprehensive insight into the molecular mechanisms involved in EC processes.
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38
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Gong C, Ai J, Fan Y, Gao J, Liu W, Feng Q, Liao W, Wu L. NCAPG Promotes The Proliferation Of Hepatocellular Carcinoma Through PI3K/AKT Signaling. Onco Targets Ther 2019; 12:8537-8552. [PMID: 31802891 PMCID: PMC6801502 DOI: 10.2147/ott.s217916] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 09/26/2019] [Indexed: 12/31/2022] Open
Abstract
Purpose Studies show that high expression of non-SMC condensin I complex subunit G (NCAPG) is associated with many tumors. In this study, we explore the mechanism by which NCAPG promotes proliferation in hepatocellular carcinoma (HCC). Patients and methods Liver cancer and paracancerous tissue specimens of 90 HCC patients were collected, and expression levels of NCAPG in these tissues and cell lines were evaluated by Western blotting and immunohistochemistry. HCC cells were transfected with siRNAs and plasmids, and pathway activators or inhibitors were added. The 5-ethynyl-2ʹ-deoxyuridine (EdU) proliferation assay was used to measure cell proliferation. Flow cytometry was used to evaluate cell apoptosis. Western blot assays were performed as a standard procedure to detect total protein expression. Treated HCC cells were subcutaneously injected into nude mice. Results Analysis using the Oncomine database showed that NCAPG was upregulated in HCC and immunohistochemistry and Western blot assays showed it was upregulated in both HCC tissues and HCC cell lines. The overexpression of NCAPG could promote HCC cell proliferation and reduce HCC cell apoptosis. More importantly, RNA-sequencing analysis predicted that NCAPG plays a role in the HCC via PI3K-AKT signaling pathway. The PI3K/AKT/FOXO4 pathway was aberrantly activated, and the expressions of apoptosis-related protein were altered when NCAPG was overexpressed or silenced both in vitro and in vivo. LY294002, a PI3K inhibitor, could eliminate the NCAPG role of promoting HCC cell proliferation and reducing HCC cell apoptosis, while 740Y-P, a PI3K activator, contributed to the opposite effect. Conclusion NCAPG functions as an oncogene in HCC and plays a role in promoting cell proliferation and antiapoptosis through activating the PI3K/AKT/FOXO4 pathway.
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Affiliation(s)
- Chengwu Gong
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Jiyuan Ai
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Yun Fan
- Department of Neurology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430000, People's Republic of China
| | - Jun Gao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Weiwei Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Qian Feng
- Department of Emergency Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Wenjun Liao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Linquan Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
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Choi YW, Nam GE, Kim YH, Yoon JE, Park JH, Kim JH, Kang SY, Park TJ. Abrogation of B-Raf V600E induced senescence by FoxM1 expression. Biochem Biophys Res Commun 2019; 516:866-871. [PMID: 31270027 DOI: 10.1016/j.bbrc.2019.06.144] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 06/26/2019] [Indexed: 12/12/2022]
Abstract
B-RafV600E oncogene mutation occurs in various cancers and is associated with tumor initiation. However, genetic modification of B-RafV600E in cells induces MAPK activation and results in oncogene-induced senescence. Overcoming the oncogene-induced senescence by B-RafV600E requires activation of another oncogene pathway, such as AKT signaling. In the present study, we explored the factors involved in overcoming the senescence program in cells activated by B-RafV600E and AKT signaling. B-RafV600E activation caused a feedback inhibition of AKT phosphorylation and resulted in downregulation of FoxM1, one of the AKT downstream components. AKT activation by PTEN downregulation induced FoxM1 expression, and co-expression of B-RafV600E and FoxM1 overcame the cellular senescence. These observations suggested that FoxM1 is critical downstream gene of AKT and functions to overcome B-RafV600E-induced senescence.
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Affiliation(s)
- Yong Won Choi
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, 443-721, South Korea
| | - Ga Eun Nam
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, South Korea; Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon, 443-721, South Korea
| | - Young Hwa Kim
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, South Korea; Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon, 443-721, South Korea
| | - Jung Eun Yoon
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, South Korea; Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon, 443-721, South Korea
| | - Ji Hee Park
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, South Korea; Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon, 443-721, South Korea
| | - Jang Hee Kim
- Department of Pathology, Ajou University Graduate School of Medicine, Suwon, 443-721, South Korea
| | - Seok Yun Kang
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, 443-721, South Korea.
| | - Tae Jun Park
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 443-721, South Korea; Department of Biomedical Science, Ajou University Graduate School of Medicine, Suwon, 443-721, South Korea.
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40
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Scioli MG, Storti G, D'Amico F, Gentile P, Fabbri G, Cervelli V, Orlandi A. The Role of Breast Cancer Stem Cells as a Prognostic Marker and a Target to Improve the Efficacy of Breast Cancer Therapy. Cancers (Basel) 2019; 11:1021. [PMID: 31330794 PMCID: PMC6678191 DOI: 10.3390/cancers11071021] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/13/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the most common form of tumor in women and the leading cause of cancer-related mortality. Even though the major cellular burden in breast cancer is constituted by the so-called bulk tumor cells, another cell subpopulation named cancer stem cells (CSCs) has been identified. The latter have stem features, a self-renewal capacity, and the ability to regenerate the bulk tumor cells. CSCs have been described in several cancer types but breast cancer stem cells (BCSCs) were among the first to be identified and characterized. Therefore, many efforts have been put into the phenotypic characterization of BCSCs and the study of their potential as prognostic indicators and therapeutic targets. Many dysregulated pathways in BCSCs are involved in the epithelial-mesenchymal transition (EMT) and are found up-regulated in circulating tumor cells (CTCs), another important cancer cell subpopulation, that shed into the vasculature and disseminate along the body to give metastases. Conventional therapies fail at eliminating BCSCs because of their quiescent state that gives them therapy resistance. Based on this evidence, preclinical studies and clinical trials have tried to establish novel therapeutic regimens aiming to eradicate BCSCs. Markers useful for BCSC identification could also be possible therapeutic methods against BCSCs. New approaches in drug delivery combined with gene targeting, immunomodulatory, and cell-based therapies could be promising tools for developing effective CSC-targeted drugs against breast cancer.
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Affiliation(s)
- Maria Giovanna Scioli
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Roma, Italy
| | - Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Roma, Italy
| | - Federico D'Amico
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Roma, Italy
| | - Pietro Gentile
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Roma, Italy
| | - Giulia Fabbri
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Roma, Italy
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Roma, Italy
| | - Augusto Orlandi
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Roma, Italy.
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Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis. Cell Death Differ 2019; 27:966-983. [PMID: 31296961 PMCID: PMC7206060 DOI: 10.1038/s41418-019-0389-3] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 06/15/2019] [Accepted: 06/24/2019] [Indexed: 12/20/2022] Open
Abstract
Breast cancer stem cells (BCSCs) are tumor initiating cells that can self-renew and are highly tumorigenic and chemoresistant. Therefore, the identification of factors critical for BCSC function is vital for the development of therapies. Here, we report that DNMT1-mediated FOXO3a promoter hypermethylation leads to downregulation of FOXO3a expression in breast cancer. FOXO3a is functionally related to the inhibition of FOXM1/SOX2 signaling and to the consequent suppression of BCSCs properties and tumorigenicity. Moreover, we found that SOX2 directly transactivates DNMT1 expression and thereby alters the methylation landscape, which in turn feedback inhibits FOXO3a expression. Inhibition of DNMT activity suppressed tumor growth via regulation of FOXO3a/FOXM1/SOX2 signaling in breast cancer. Clinically, we observed a significant inverse correlation between FOXO3a and FOXM1/SOX2/DNMT1 expression levels, and loss of FOXO3a expression or increased expression of FOXM1, SOX2, and DNMT1 predicted poor prognosis in breast cancer. Collectively, our findings suggest an important role of the DNMT1/FOXO3a/FOXM1/SOX2 pathway in regulating BCSCs properties, suggesting potential therapeutic targets for breast cancer.
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Nazio F, Bordi M, Cianfanelli V, Locatelli F, Cecconi F. Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications. Cell Death Differ 2019; 26:690-702. [PMID: 30728463 PMCID: PMC6460398 DOI: 10.1038/s41418-019-0292-y] [Citation(s) in RCA: 283] [Impact Index Per Article: 47.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 01/15/2019] [Accepted: 01/16/2019] [Indexed: 02/07/2023] Open
Abstract
Autophagy and mitophagy act in cancer as bimodal processes, whose differential functions strictly depend on cancer ontogenesis, progression, and type. For instance, they can act to promote cancer progression by helping cancer cells survive stress or, instead, when mutated or abnormal, to induce carcinogenesis by influencing cell signaling or promoting intracellular toxicity. For this reason, the study of autophagy in cancer is the main focus of many researchers and several clinical trials are already ongoing to manipulate autophagy and by this way determine the outcome of disease therapy. Since the establishment of the cancer stem cell (CSC) theory and the discovery of CSCs in individual cancer types, autophagy and mitophagy have been proposed as key mechanisms in their homeostasis, dismissal or spread, even though we still miss a comprehensive view of how and by which regulatory molecules these two processes drive cell fate. In this review, we will dive into the deep water of autophagy, mitophagy, and CSCs and offer novel viewpoints on possible therapeutic strategies, based on the modulation of these degradative systems.
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Affiliation(s)
- Francesca Nazio
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
| | - Matteo Bordi
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
- Department of Biology, University of Tor Vergata, 00133, Rome, Italy
| | - Valentina Cianfanelli
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, 2100, Copenhagen, Denmark
| | - Franco Locatelli
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy
- Department of Gynecology/Obstetrics and Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Francesco Cecconi
- Department of Oncohaematology and Cellular and Gene Therapy, IRCSS Bambino Gesù Children's Hospital, 00165, Rome, Italy.
- Department of Biology, University of Tor Vergata, 00133, Rome, Italy.
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, 2100, Copenhagen, Denmark.
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Twomey JD, Zhang B. Circulating Tumor Cells Develop Resistance to TRAIL-Induced Apoptosis Through Autophagic Removal of Death Receptor 5: Evidence from an In Vitro Model. Cancers (Basel) 2019; 11:cancers11010094. [PMID: 30650534 PMCID: PMC6356356 DOI: 10.3390/cancers11010094] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 01/08/2019] [Accepted: 01/08/2019] [Indexed: 01/03/2023] Open
Abstract
Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood. This study aims at understanding the molecular features within CTCs, in relation to their metastatic potential. Using in vitro CTC models, in which breast cancer cell lines were cultured in non-adherent conditions simulating the microenvironment in the blood stream, we found that the suspension culture resulted in resistance to TNF-related apoptosis inducing ligand (TRAIL)-mediated cell death. Such a resistance was directly correlated with a reduction in surface and total levels of DR5 protein. In the non-adherent state, the cells underwent a rapid autophagic flux, characterized by an accumulation of autophagosome organelles. Notably, DR5 was translocated to the autophagosomes and underwent a lysosomal degradation. Our data suggest that CTCs may evade the TNF cytokine-mediated immune surveillance through a downregulation of the death receptor (DR) expression. The data warrants further studies in cancer patients to find the status of DRs and other molecular features within primary CTCs, in relation to disease progression or chemoresistance.
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Affiliation(s)
- Julianne D Twomey
- Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
| | - Baolin Zhang
- Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
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44
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Wang X, Fang L. Advances in circular RNAs and their roles in breast Cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:206. [PMID: 30157902 PMCID: PMC6116371 DOI: 10.1186/s13046-018-0870-8] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 04/08/2018] [Indexed: 12/21/2022]
Abstract
Circular RNAs (circRNAs) are a type of noncoding RNAs with a closed loop structure. With the development of high-throughput sequencing, massive circRNAs have been discovered in tumorous tissues. Emerging evidence suggests that the biological functions of circRNAs including serving as ceRNAs or miRNA sponges, interacting with proteins, regulating gene transcription and translation, suggesting that circRNAs will be novel biomarkers and targets for the diagnosis and prognosis of diseases. Breast cancer is the most frequently occurring cancer and the leading cause of cancer-related death among women worldwide. It is vital to understand the molecular pathways involved in the pathogenesis of proliferation and progression. In this review, we summarize the current knowledge on human circRNAs and their potential clinical implications on breast cancer.
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Affiliation(s)
- Xuehui Wang
- Nanjing Medical University, Nanjing, 211166, China.,Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Shanghai, 200070, China
| | - Lin Fang
- Department of Thyroid and Breast Surgery, Shanghai Tenth People's Hospital, Shanghai, 200070, China.
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45
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Yu A, Wang Y, Bian Y, Chen L, Guo J, Shen W, Chen D, Liu S, Sun X. IL-1β promotes the nuclear translocaiton of S100A4 protein in gastric cancer cells MGC803 and the cell's stem-like properties through PI3K pathway. J Cell Biochem 2018; 119:8163-8173. [PMID: 29932233 DOI: 10.1002/jcb.26813] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 02/23/2018] [Indexed: 12/16/2022]
Abstract
It has been shown that nuclear expression of S100A4 is significantly correlated with increased metastasis and reduced survival in patients with gastric cancer and many other cancers. However, the factors which could influence the nuclear contents of S100A4 in cancer cells are not clear. It has also been reported that Interleukin-1β (IL-1β) promotes the nuclear translocation of S100A4 in chondrocytes. Previous studies have shown that IL-1β promotes the stemness of colon cancer cells, and S100A4 is also involved in maintaining cancer-initiating cells in head and neck cancers. We speculate that IL-1β might promote the nuclear translocation of S100A4 protein in MGC803 gastric cancer cells and therefore enhance their stem-like properties. The results from Western-blot and qRT-PCR analysis showed that IL-1β increased the nuclear and total cellular content of S100A4 protein and S100A4 mRNA level in MGC803 cells. LY294002, a pharmacological inhibitor of Phosphoinositide 3-kinase (PI3K) reversed the above effects. Functional studies indicated that IL-1β promoted the colony-forming and spheroid-forming capabilities of the cells and the expression of SOX2 and NANOG gene. PI3K or S100A4 inhibition reversed the IL-1β-mediated increase in colony and spheroid-forming capabilities of the cells. LY294002 also reversed the elevated SOX2 and NANOG expression induced by IL-1β. Our study demonstrated that IL-1β promote the nuclear translocation of S100A4 protein in gastric cancer cells MGC803, which are PI3K dependent, suggesting the existence of IL-1β-PI3K-S100A4 pathway for the first time. The study also showed that IL-1β promoted stem-like properties of the cells through the new pathway.
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Affiliation(s)
- Aiwen Yu
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.,Department of Rehabilitation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yu Wang
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Yue Bian
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Lisha Chen
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Junfu Guo
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Wei Shen
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Danqi Chen
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Shanshan Liu
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
| | - Xiuju Sun
- Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China
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46
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Wang D, Yang S, Wang H, Wang J, Zhang Q, Zhou S, He Y, Zhang H, Deng F, Xu H, Zhong S, Fu L, Tang J. The progress of circular RNAs in various tumors. Am J Transl Res 2018; 10:1571-1582. [PMID: 30018701 PMCID: PMC6038087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 04/06/2018] [Indexed: 06/08/2023]
Abstract
Circular RNAs (circRNAs), a novel type of non-coding RNAs, presented as covalently closed continuous loops. Recent researches had found that circRNAs could function as microRNA sponges, regulators of gene transcription and encoding proteins. They were relatively stable and expressed widely in cytoplasm, which played important roles in carcinogenesis of cancers, such as esophageal cancer, gastric cancer, colorectal cancer, hepatocarcinoma, bladder cancer, glioma, breast cancer, osteosarcoma and so on. Furthermore, they were involved in many biological functions, like cell proliferation, drug resistance, cell cycle, invasion and metastasis. Therefore, the further studies were meaningful on the mechanism of cancers and circRNAs. In the review, we will summarize the current biogenesis of circRNAs and the roles of them in various cancers, which might be a novel biomarker and therapeutic avenue.
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Affiliation(s)
- Dandan Wang
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029, China
| | - Sujin Yang
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029, China
| | - Hui Wang
- Jiangsu Jiankang Vocational CollegeNanjing 210000, China
| | - Jinyan Wang
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029, China
| | - Qian Zhang
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029, China
| | - Siying Zhou
- The First Clinical Medical College, Nanjing University of Traditional Chinese MedicineNanjing 210023, China
| | - Yunjie He
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029, China
| | - Heda Zhang
- Department of General Surgery, Southeast University Medical SchoolNanjing 210009, China
| | - Fei Deng
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029, China
| | - Hanzi Xu
- Department of Radiation Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical UniversityNanjing 210009, China
| | - Shanliang Zhong
- Center of Clinical Laboratory Science, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing 210009, China
| | - Li Fu
- Department of Breast Cancer Pathology and Research Laboratory, Key Laboratory of Breast Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and HospitalTianjin, China
| | - Jinhai Tang
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical UniversityNanjing 210029, China
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Hornsveld M, Dansen T, Derksen P, Burgering B. Re-evaluating the role of FOXOs in cancer. Semin Cancer Biol 2018; 50:90-100. [DOI: 10.1016/j.semcancer.2017.11.017] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 10/23/2017] [Accepted: 11/20/2017] [Indexed: 02/07/2023]
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48
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Maleki E, Ghaedi K, Shahanipoor K, Karimi Kurdistani Z. Down-regulation of microRNA-19b in hormone receptor-positive/HER2-negative breast cancer. APMIS 2018; 126:303-308. [PMID: 29575198 DOI: 10.1111/apm.12820] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 01/21/2018] [Indexed: 12/19/2022]
Abstract
miR-19b (miR-19b-3p) has been reported to be correlated with either favorable or unfavorable events in several cancers. However, no study has been conducted to evaluate the expression level of miR-19b in patients with breast cancer (BC). This study was aimed to investigate the expression level of miR-19b in human malignant and healthy breast tissues with histopathology of ER+/PR+/HER2-. We performed a miRNA real-time PCR to detect differential expression of miR-19b in 40 BC, including 17 BC with familial background and 23 BC without familial background, and 12 non-tumoral tissues. Moreover, a bioinformatics prediction upon miR-19b functionality in BC cells was performed. The miR-19b expression level was significantly down-regulated in BC, BC with familial background, and BC without familial background compared with its expression in normal tissue (p value, <0.0001; fold change, -7.45; p value, 0.0003; fold change, -6.45; and p value, 0.0005; fold change, -8.41, respectively). Moreover, according to the AUCs (area under curve) of receiver operating characteristic (ROC) curves, miR-19b can significantly distinguish all defined categories. Last, in agreement with our experimental findings, proteoglycans in cancer, pathways in cancer, FoxO signaling pathway, central carbon metabolism in cancer, p53 signaling pathway, transcriptional misregulation in cancer, and prolactin signaling pathway were predicted as miR-19b-related signaling pathways. In summary, down-regulation of miR-19b in BC vs healthy tissue suggests that mir-19b can function as a tumor suppressor. Our results shed additional information on controversial expression pattern of miR-19b depending on different cancer types.
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Affiliation(s)
- Elham Maleki
- Department of Biochemistry, Islamic Azad University, Falavarjan Branch, Isfahan, Iran
| | - Kamran Ghaedi
- Cellular and Molecular Biology Division, Biology Department, Faculty of Sciences, University of Isfahan, Isfahan, Iran
| | - Kahin Shahanipoor
- Department of Biochemistry, Islamic Azad University, Falavarjan Branch, Isfahan, Iran
| | - Zana Karimi Kurdistani
- Department of Biology, College of Basic Sciences, Islamic Azad University, Sanandaj Branch, Kurdistan, Iran
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Abstract
Resistance to chemotherapy and cancer relapse are major clinical challenges attributed to a sub population of cancer stem cells (CSCs). The concept of CSCs has been the subject of intense research by the oncology community since evidence for their existence was first published over twenty years ago. Emerging data indicates that they are also able to evade novel therapies such as targeted agents, immunotherapies and anti-angiogenics. The inability to appropriately identify and isolate CSCs is a major hindrance to the field and novel technologies are now being utilized. Agents that target CSC-associated cell surface receptors and signaling pathways have generated promising pre-clinical results and are now entering clinical trial. Here we discuss and evaluate current therapeutic strategies to target CSCs.
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Affiliation(s)
- Stephanie Annett
- Molecular and Cellular Therapeutics, Royal College of Surgeons Ireland, Ireland
| | - Tracy Robson
- Molecular and Cellular Therapeutics, Royal College of Surgeons Ireland, Ireland.
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50
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Firat E, Niedermann G. FoxO proteins or loss of functional p53 maintain stemness of glioblastoma stem cells and survival after ionizing radiation plus PI3K/mTOR inhibition. Oncotarget 2018; 7:54883-54896. [PMID: 27448972 PMCID: PMC5342388 DOI: 10.18632/oncotarget.10702] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 06/12/2016] [Indexed: 01/08/2023] Open
Abstract
Dual PI3K/mTOR inhibitors do not effectively radiosensitize glioblastoma multiforme stem cells (GBM-SCs), but p53-proficient GBM-SCs are more responsive than p53-deficient ones. Here, we found that p53-proficient, but not p53-deficient, GBM-SCs lost stemness and differentiated after γ-irradiation combined with PI3K/mTOR inhibition; expression of FoxO proteins was also lost. FoxO overexpression inhibited the loss of stem cell markers under these conditions. Combined, but not single, FoxO1/3 deletion or pharmacological inhibition of FoxO transcriptional activity strongly reduced stem and progenitor marker expression, particularly that of Sox2. Binding of FoxO1 and FoxO3 to the sox2 regulatory regions was also found. However, combined FoxO1/3 knockdown strongly reduced self-renewal and post-treatment survival only in p53-proficient GBM-SCs. This suggests that FoxO1 and FoxO3 are crucial for functional stemness and post-treatment survival mainly in p53-proficient but not in p53-deficient GBM-SCs, and that these functions can be maintained through the loss of DNA damage-responsive p53 instead.
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Affiliation(s)
- Elke Firat
- Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany
| | - Gabriele Niedermann
- Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK), Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
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