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Yang R, Wang H, Wu C, Shi Y, Li H, Bao X, Yang Y, Han S, Yang X, Tao J, Sun H, Wu S, Sun L. PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling. Biomark Res 2025; 13:70. [PMID: 40336138 PMCID: PMC12060467 DOI: 10.1186/s40364-025-00785-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/26/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Progesterone and adipose Q receptor 5 (PAQR5), a membrane receptor characterized by seven transmembrane domains, has been indirectly implicated in pro-carcinogenic activities, though its specific role in hepatocellular carcinoma (HCC) remains to be defined. METHODS This study aimed to elucidate the molecular mechanisms by which PAQR5 facilitates HCC progression and contributes to the immunosuppressive microenvironment through an integrative approach combining multi-omics analysis and experimental validation. Utilizing data from bulk, single-cell, and spatial transcriptomics cohorts, this study systematically assessed the expression patterns, immune landscape, and functional characteristics of PAQR5 across different levels of resolution in HCC. RESULTS PAQR5 expression was significantly upregulated in tumor tissues and correlated with poor clinical outcomes. Enrichment analysis revealed that PAQR5 activated the NF-κB signaling pathway in HCC. Single-cell transcriptomics identified PAQR5 as predominantly localized within malignant cell clusters, with significant association with NF-κB pathway activation. Spatial transcriptomics further corroborated the alignment of PAQR5 expression with tumor cell distribution. In vitro assays showed elevated PAQR5 levels in HCC cell lines, and silencing PAQR5 significantly suppressed cell proliferation, invasion, epithelial-mesenchymal transition (EMT), and prevented the formation of immunosuppressive microenvironment. In vivo studies demonstrated that targeting PAQR5 attenuated tumorigenic potential, disrupted the invasion-metastasis cascade and inhibited the tumor immune escape. Mechanistically, PAQR5 was found to activate NF-κB signaling by inducing ERK phosphorylation, thereby driving proliferation, invasion, EMT, and immune escape in HCC through the pathway.
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Affiliation(s)
- Ruida Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
- Department of Thoracic Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huanhuan Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Cong Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yu Shi
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Hanqi Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Xinyue Bao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yuqian Yang
- Department of Medical Oncology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 711018, Shaanxi, People's Republic of China
| | - Shaoshan Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Xue Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Jie Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Hao Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
| | - Shaobo Wu
- Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
| | - Liankang Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [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: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Ghnim ZS, Mahdi MS, Ballal S, Chahar M, Verma R, Al-Nuaimi AMA, Kumar MR, Al-Hussein RKA, Adil M, Jawad MJ. The role of kinesin superfamily proteins in hepatocellular carcinoma. Med Oncol 2024; 41:271. [PMID: 39400594 DOI: 10.1007/s12032-024-02497-0] [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: 07/29/2024] [Accepted: 09/04/2024] [Indexed: 10/15/2024]
Abstract
The most prevalent form of primary liver cancer, hepatocellular carcinoma (HCC) poses a significant global health challenge due to its limited therapeutic options. Researchers are currently focused on the complex molecular landscape that governs the initiation and progression of HCC in order to identify new avenues for diagnosis, prognosis, and treatment. In the context of HCC, the Kinesin Superfamily Proteins (KIFs) have become critical regulators of cellular processes, prompting a growing interest in their function among the diverse array of molecular actors implicated in cancer. The KIFs, a family of microtubule-based molecular motors, are renowned for their essential roles in the dynamics of mitotic spindles and intracellular transport. Beyond their well-established functions in normal cellular physiology, emerging evidence indicates that dysregulation of KIFs significantly contributes to the pathogenesis of HCC. Novel therapeutic targets and diagnostic markers are revealed through the unique opportunity to comprehend the complex interplay between KIFs and the molecular events that drive HCC.
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Affiliation(s)
| | | | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India.
| | - Mamata Chahar
- Department of Chemistry, NIMS Institute of Engineering & Technology, NIMS University, Jaipur, Rajasthan, India
| | - Rajni Verma
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges, Jhanjeri, Mohali, Amritsar, Punjab, 140307, India
| | | | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | | | - Mohaned Adil
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Ahmad A, Tiwari RK, Siddiqui S, Chadha M, Shukla R, Srivastava V. Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:41-99. [PMID: 38663962 DOI: 10.1016/bs.ircmb.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.
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Affiliation(s)
- Afza Ahmad
- Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Rohit Kumar Tiwari
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Saleha Siddiqui
- Department of Biotechnology, Delhi Technological University, Delhi, India
| | - Muskan Chadha
- Department of Nutrition and Dietetics, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Ratnakar Shukla
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vivek Srivastava
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Greater Noida, Uttar Pradesh, India.
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Chen S, Zhou B, Huang W, Li Q, Yu Y, Kuang X, Huang H, Wang W, Xie P. The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression. Cell Death Dis 2023; 14:830. [PMID: 38097536 PMCID: PMC10721641 DOI: 10.1038/s41419-023-06358-y] [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: 07/27/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world. Research into the key genes that maintain the malignant behavior of cancer cells is crucial for the treatment of HCC. Here, we identified ubiquitin-specific peptidase 44 (USP44), a member of the deubiquitinase family, as a novel regulator of HCC progression. The tumor suppressive function of USP44 was evaluated in a series of in vitro and in vivo experiments. Through quantitative proteomics examination, we demonstrated that USP44 inhibits HCC PDL1 expression by downregulating the Hedgehog (Hh) signaling pathway. Mechanistically, we found that USP44 directly interacts with Itch, an E3 ligase involved in Hh signaling, and promotes the deubiquitination and stabilization of Itch. These events result in the proteasomal degradation of Gli1 and subsequent inactivation of Hh signaling, which ultimately suppresses PDL1 expression and the progression of HCC. Furthermore, the HCC tissue microarray was analyzed by immunohistochemistry to evaluate the pathological relevance of the USP44/Itch/Gli1/PDL1 axis. Finally, the Gli1 inhibitor GANT61 was found to act in synergy with anti-PDL1 therapy. Overall, USP44 can act as a suppressive gene in HCC by modulating Hh signaling, and co-inhibition of Gli1 and PDL1 might be an effective novel combination strategy for treating HCC patients.
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Affiliation(s)
- Sisi Chen
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Binghai Zhou
- Hepato-Biliary-Pancreatic Surgery Division, Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Wei Huang
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Qing Li
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Ye Yu
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Xiuqing Kuang
- Department of Physical Examination, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Huabin Huang
- Department of Medical Imaging, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China
| | - Wei Wang
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China.
| | - Peiyi Xie
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
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6
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Nguyen TH, Nguyen TM, Ngoc DTM, You T, Park MK, Lee CH. Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions. Int J Mol Sci 2023; 24:16255. [PMID: 38003445 PMCID: PMC10671265 DOI: 10.3390/ijms242216255] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
This review aims to provide a comprehensive understanding of the molecular mechanisms underlying autophagy and mitophagy in hepatocellular carcinoma (HCC). Autophagy is an essential cellular process in maintaining cell homeostasis. Still, its dysregulation is associated with the development of liver diseases, including HCC, which is one of leading causes of cancer-related death worldwide. We focus on elucidating the dual role of autophagy in HCC, both in tumor initiation and progression, and highlighting the complex nature involved in the disease. In addition, we present a detailed analysis of a small subset of autophagy- and mitophagy-related molecules, revealing their specific functions during tumorigenesis and the progression of HCC cells. By understanding these mechanisms, we aim to provide valuable insights into potential therapeutic strategies to manipulate autophagy effectively. The goal is to improve the therapeutic response of liver cancer cells and overcome drug resistance, providing new avenues for improved treatment options for HCC patients. Overall, this review serves as a valuable resource for researchers and clinicians interested in the complex role of autophagy in HCC and its potential as a target for innovative therapies aimed to combat this devastating disease.
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Affiliation(s)
- Thi Ha Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | | | - Taesik You
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Mi Kyung Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cance Center, Goyang 10408, Republic of Korea
- Department of Bio-Healthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
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Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev 2023; 42:629-652. [PMID: 36729264 DOI: 10.1007/s10555-023-10084-4] [Citation(s) in RCA: 145] [Impact Index Per Article: 72.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/16/2023] [Indexed: 02/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.
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Affiliation(s)
- Yu Wang
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China
| | - Baocheng Deng
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China.
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Yao Y, Li T, Yu T, Yang X, Wang Y, Cai J, Cheng SY, Liu C, Yue S. Hedgehog signal activates AMPK via Smoothened to promote autophagy and lipid degradation in hepatocytes. Biochem Cell Biol 2023; 101:284-293. [PMID: 36821837 DOI: 10.1139/bcb-2022-0345] [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] [Indexed: 02/25/2023] Open
Abstract
Studies in the past decade have shown that lipid droplets stored in liver cells under starvation are encapsulated by autophagosomes and fused to lysosomes via the endocytic system. Autophagy responds to a variety of environmental factors inside and outside the cell, so it has a complex signal regulation network. To this end, we first explored the role of Hedgehog (Hh) in autophagy and lipid metabolism. Treatment of normal mouse liver cells with SAG and GDC-0449 revealed elevated phosphorylation of AMP-activated protein kinase (AMPK) and increased lipidation of LC3. SAG, and GDC-0449 were agonist and antagonist of Smoothened (Smo) in canonical Hh pathway, respectively, but they played a consistent role in the regulation of autophagy in hepatocytes. Moreover, SAG and GDC-0449 did not affect the expression of glioma-associated oncogene (Gli1) and patched 1, suggesting the absence of canonical Hh signaling in hepatocytes. We further knocked down the Smo and found that the effects of SAG and GDC-0449 disappeared, indicating that the non-canonical Smo pathway was involved in the regulation of autophagy in hepatocytes. In addition, SAG and GDC-0449 promoted lipid degradation and inhibited lipid production signals. Knockdown of Smo slowed down the rate of lipid degradation rather than Sufu or Gli1, indicating that Hh signaling regulated the lipid metabolism via Smo. In summary, activates AMPK via Smo to promote autophagy and lipid degradation.
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Affiliation(s)
- Yixing Yao
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
- Department of Pathology, Suzhou Ninth People's Hospital, Suzhou 215200, China
| | - Tianyuan Li
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
| | - Tingting Yu
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
| | - Xin Yang
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
| | - Yue Wang
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
| | - Jing Cai
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
| | - Steven Y Cheng
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Chen Liu
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
| | - Shen Yue
- Department of Medical Genetics, Nanjing Medical University, Nanjing 211166, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China
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Sun Y, Fang Q, Liu W, Liu Y, Zhang C. GANT-61 induces cell cycle resting and autophagy by down-regulating RNAP III signal pathway and tRNA-Gly-CCC synthesis to combate chondrosarcoma. Cell Death Dis 2023; 14:461. [PMID: 37488121 PMCID: PMC10366213 DOI: 10.1038/s41419-023-05926-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 06/17/2023] [Accepted: 06/23/2023] [Indexed: 07/26/2023]
Abstract
Chondrosarcoma is ineffective for conventional radiotherapy and chemotherapy with a poor prognosis. Hedgehog (Hh) signal pathway plays a crucial role in tumor growth and progression, which is constitutive activated in chondrosarcoma. GLI transcription factors as targets for new drugs or interference technology for the treatment of chondrosarcoma are of great significance. In this study, we indicated that the Hedgehog-GLI1 signal pathway is activated in chondrosarcoma, which further enhances the RNAP III signal pathway to mediate endogenous tRNA fragments synthesis. Downstream oncology functions of endogenous tRNA fragments, such as "cell cycle" and "death receptor binding", are involved in malignant chondrosarcoma. The GANT-61, as an inhibitor of GLI1, could inhibit chondrosarcoma tumor growth effectively by inhibiting the RNAP III signal pathway and tRNA-Gly-CCC synthesis in vivo. Induced G2/M cell cycle resting, apoptosis, and autophagy were the main mechanisms for the inhibitory effect of GANT-61 on chondrosarcoma, which correspond with the above-described downstream oncology functions of endogenous tRNA fragments. We also identified the molecular mechanism by which GANT-61-induced autophagy is involved in ULK1 expression and MAPK signaling pathway. Thus, GANT-61 will be an ideal and promising strategy for combating chondrosarcoma.
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Affiliation(s)
- Yifeng Sun
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, 250014, PR China
- Department of Surgery, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
- Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany
| | - Qiongxuan Fang
- MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Wei Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, 250014, PR China
| | - Yi Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, 250014, PR China
| | - Chunming Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University &Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, 250014, PR China.
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10
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Liu S, Kang L, Song Y, Miao M. Role of the HIF-1α/BNIP3 Signaling Pathway in Recurrent Hepatocellular Carcinoma and the Mechanism of Traditional Chinese Medicine. J Hepatocell Carcinoma 2023; 10:893-908. [PMID: 37313302 PMCID: PMC10259603 DOI: 10.2147/jhc.s409292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 06/01/2023] [Indexed: 06/15/2023] Open
Abstract
Recurrence of hepatocellular carcinoma (HCC) negatively affects the quality of life of patients and leads to death. Studies have shown that recurrent hepatocellular carcinoma (RHCC) is closely related to tissue hypoxia and autophagy. It has been shown that hypoxia-inducible factor-1α (HIF-1α) and its downstream factor BCL-2 19 kDa-interacting protein 3 (BNIP3) promote cellular autophagy under hypoxic conditions, resulting in metastasis and RHCC. In this article, the molecular structures of HIF-1α and BNIP3 are described, and the significance of the HIF-1α/BNIP3 signaling pathway in RHCC is explained. Moreover, the role and mechanism of traditional Chinese medicine (TCM) in treating RHCC by modulating the HIF-1α/BNIP3 signaling pathway is discussed. Studies have shown that the HIF-1α/BNIP3 signaling pathway is a potential target of TCM in the treatment of RHCC. The mechanism of the HIF-1α/BNIP3 signaling pathway in RHCC and the progress achieved in TCM research on targeting and regulating this pathway are also reviewed in this article. The objective was to provide a theoretical basis for the prevention and treatment of RHCC, as well as further drug development.
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Affiliation(s)
- Sizhe Liu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China
| | - Le Kang
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China
| | - Yagang Song
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China
| | - Mingsan Miao
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China
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Jiang Y, Zhou Y, Xu W, Wang X, Jin H, Bao X, Lu C. Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy. Cell Biol Toxicol 2023; 39:729-749. [PMID: 34405320 DOI: 10.1007/s10565-021-09635-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/13/2021] [Indexed: 01/16/2023]
Abstract
Hepatocyte senescence is a key event participating in the progression of alcoholic liver disease. Autophagy is a critical biological process that controls cell fates by affecting cell behaviors like senescence. Pterostilbene is a natural compound with hepatoprotective potential; however, its implication for alcoholic liver disease was not understood. This study was aimed to investigate the therapeutic effect of pterostilbene on alcoholic liver disease and elucidate the potential mechanism. Our results showed that pterostilbene alleviated ethanol-triggered hepatocyte damage and senescence. Intriguingly, pterostilbene decreased the protein abundance of cellular communication network factor 1 (CCN1) in ethanol-exposed hepatocytes, which was essential for pterostilbene to execute its anti-senescent function. In vivo studies verified the anti-senescent effect of pterostilbene on hepatocytes of alcohol-intoxicated mice. Pterostilbene also relieved senescence-associated secretory phenotype (SASP), redox imbalance, and steatosis by suppressing hepatic CCN1 expression. Mechanistically, pterostilbene-forced CCN1 reduction was dependent on posttranscriptional regulation via autophagy machinery but not transcriptional regulation. To be specific, pterostilbene restored autophagic flux in damaged hepatocytes and activated p62-mediated selective autophagy to recognize and lead CCN1 to autolysosomes for degradation. The protein abundance of Sestrin2 (SESN2), a core upstream modulator of autophagy pathway, was decreased in ethanol-administrated hepatocytes but rescued by co-treatment with pterostilbene. Induction of SESN2 protein by pterostilbene rescued ethanol-triggered autophagic dysfunction in hepatocytes, which then reduced senescence-associated markers, postponed hepatocyte senescence, and relieved alcohol-caused liver injury and inflammation. In conclusion, this work discovered a novel compound pterostilbene with therapeutic implications for alcoholic liver disease and uncover its underlying mechanism.
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Affiliation(s)
- Yiming Jiang
- School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Ying Zhou
- School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Wenxuan Xu
- School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, Jiangsu, China
| | - Xinqi Wang
- School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Huanhuan Jin
- Department of Pharmacology, School of Pharmacy, Wannan Medical College, 22 West Wenchang Road, Wuhu, 241002, Anhui, China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China.
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12
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Design, synthesis and pharmacological evaluation of β-carboline derivatives as potential antitumor agent via targeting autophagy. Eur J Med Chem 2023; 246:114955. [PMID: 36459757 DOI: 10.1016/j.ejmech.2022.114955] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/10/2022] [Accepted: 11/20/2022] [Indexed: 11/27/2022]
Abstract
A series of novel β-carboline derivatives was designed, synthesized and evaluated as potential anticancer agents. Among them, compound 6g showed the most potent antiproliferative activity against the 786-0, HT-29 and 22RV1 cell lines with IC50 values of 2.71, 2.02, and 3.86 μM, respectively. The antitumor efficiency of compound 6gin vivo was also evaluated, and the results revealed that compound 6g significantly suppressed tumor development and reduced tumor weight in a mouse colorectal cancer homograft model. Further investigation on mechanisms of action demonstrated that compound 6g inhibited HCT116 cell growth by stimulating the ATG5/ATG7-dependent autophagic pathway. These molecules might be served as candidates for further development of colorectal cancer therapy agent.
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13
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CRC Therapy Identifies Indian Hedgehog Signaling in Mouse Endometrial Epithelial Cells and Inhibition of Ihh-KLF9 as a Novel Strategy for Treating IUA. Cells 2022; 11:cells11244053. [PMID: 36552817 PMCID: PMC9776583 DOI: 10.3390/cells11244053] [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: 10/29/2022] [Revised: 11/26/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Intrauterine adhesion (IUA) causes menstrual disturbance and infertility. There is no effective treatment available for moderate to severe IUA cases. Stem cell-based therapy has been investigated for treating IUA but is limited in clinical applications due to issues including the precise induction of differentiation, tumorigenesis, and unclear molecular mechanisms. In our recent study, we isolated and expanded the long-term cultures of conditional reprogrammed (CR) mouse endometrial epithelial cells. Treating IUA mice with these CR cells (CRCs) restored the morphology and structure of the endometrium and significantly improved the pregnancy rate. In this study, our data with high-throughput sequencing, CRISPR knockout Ihh-/-CRCs, and transplantation identified for the first time that the Indian hedgehog (Ihh) gene plays a critical role in the regulation of endometrial epithelial cell proliferation. We also found that aberrant activated Ihh-krüppel-like factor 9 (KLF9) signaling contributes to the inhibition of normal progesterone receptor (PR) function in IUA mice. Thus, we hypothesized that inhibition of the Ihh-KLF9 pathway may be a novel strategy to treat IUA. Our data demonstrated that treatment with the hedgehog signaling inhibitor Vismodegib restored the morphology, structure, and microenvironment of the endometrium, and greatly improved the pregnancy rate in IUA mice. This study suggests a promising application of hedgehog inhibitors as a targeted drug in the IUA clinic.
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Modulation of Hedgehog Signaling for the Treatment of Basal Cell Carcinoma and the Development of Preclinical Models. Biomedicines 2022; 10:biomedicines10102376. [PMID: 36289637 PMCID: PMC9598418 DOI: 10.3390/biomedicines10102376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/17/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022] Open
Abstract
Basal Cell Carcinoma (BCC) is the most commonly diagnosed cancer worldwide. While the survivability of BCC is high, many patients are excluded from clinically available treatments due to health risks or personal choice. Further, patients with advanced or metastatic disease have severely limited treatment options. The dysregulation of the Hedgehog (Hh) signaling cascade drives onset and progression of BCC. As such, the modulation of this pathway has driven advancements in BCC research. In this review, we focus firstly on inhibitors that target the Hh pathway as chemotherapeutics against BCC. Two therapies targeting Hh signaling have been made clinically available for BCC patients, but these treatments suffer from limited initial efficacy and a high rate of chemoresistant tumor recurrence. Herein, we describe more recent developments of chemical scaffolds that have been designed to hopefully improve upon the available therapeutics. We secondly discuss the history and recent efforts involving modulation of the Hh genome as a method of producing in vivo models of BCC for preclinical research. While there are many advancements left to be made towards improving patient outcomes with BCC, it is clear that targeting the Hh pathway will remain at the forefront of research efforts in designing more effective chemotherapeutics as well as relevant preclinical models.
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15
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Núñez KG, Sandow T, Lakey MA, Fort D, Cohen AJ, Thevenot PT. Distinct Gene Expression Profiles in Viable Hepatocellular Carcinoma Treated With Liver-Directed Therapy. Front Oncol 2022; 12:809860. [PMID: 35785174 PMCID: PMC9248864 DOI: 10.3389/fonc.2022.809860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 05/13/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma is a heterogeneous tumor that accumulates a mutational burden and dysregulated signaling pathways that differ from early to advanced stages. Liver transplant candidates with early-stage hepatocellular carcinoma (HCC) undergo liver-directed therapy (LDT) to delay disease progression and serve as a bridge to liver transplantation (LT). Unfortunately, >80% of LDT-treated patients have viable HCC in the explant liver, dramatically increasing recurrence risk. Understanding the effect of LDT on early-stage HCC could help identify therapeutic targets to promote complete pathologic necrosis and improve recurrence-free survival. In this study, transcriptomic data from viable HCC in LDT-treated bridged to transplant patients were investigated to understand how treatment may affect tumor signaling pathways. METHODS Multiplex transcriptomic gene analysis was performed with mRNA extracted from viable tumors of HCC patients bridged to transplant using LDT. The NanoString nCounter® Tumor Signaling 360 panel was used that contained 780 genes from 48 pathways involved in tumor biology within the microenvironment as well as antitumoral immune responses. RESULTS Hierarchical clustering separated tumors into three subtypes (HCC-1, HCC-2, and HCC-3) each with distinct differences in anti-tumoral signaling and immune infiltration within the tumor microenvironment. Immune infiltration (neutrophils, T cells, and macrophages) were all lowest in subtype HCC-3. The tumor inflammatory signature consisting of 18 genes associated with PD-1/PD-L1 inhibition, antigen presentation, chemokine secretion, and adaptive immune responses was highest in subtype HCC-1 and lowest in HCC-3. History of decompensation and etiology were associated with HCC subtype favoring downregulations in inflammation and immune infiltration with upregulation of lipid metabolism. Gene expression among intrahepatic lesions was remarkably similar with >85% of genes expressed in both lesions. Genes differentially expressed (<8 genes per patient) in multifocal disease were all upregulated in LDT-treated tumors from pathways involving epithelial mesenchymal transition, extracellular matrix remodeling, and/or inflammation potentially implicating intrahepatic metastases. CONCLUSION Incomplete response to LDT may drive expression patterns that inhibit an effective anti-tumoral response through immune exclusion and induce intrahepatic spread.
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Affiliation(s)
- Kelley G. Núñez
- Institute of Translational Research, Ochsner Health System, New Orleans, LA, United States
| | - Tyler Sandow
- Interventional Radiology, Ochsner Health System, New Orleans, LA, United States
| | - Meredith A. Lakey
- Ochsner Biorepository, Ochsner Health System, New Orleans, LA, United States
| | - Daniel Fort
- Centers for Outcomes and Health Services Research, Ochsner Health System, New Orleans, LA, United States
| | - Ari J. Cohen
- Multi-Organ Transplant Institute, Ochsner Health System, New Orleans, LA, United States
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Paul T. Thevenot
- Institute of Translational Research, Ochsner Health System, New Orleans, LA, United States
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16
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Senatore E, Iannucci R, Chiuso F, Delle Donne R, Rinaldi L, Feliciello A. Pathophysiology of Primary Cilia: Signaling and Proteostasis Regulation. Front Cell Dev Biol 2022; 10:833086. [PMID: 35646931 PMCID: PMC9130585 DOI: 10.3389/fcell.2022.833086] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 04/21/2022] [Indexed: 01/29/2023] Open
Abstract
Primary cilia are microtubule-based, non-motile sensory organelles present in most types of growth-arrested eukaryotic cells. They are transduction hubs that receive and transmit external signals to the cells in order to control growth, differentiation and development. Mutations of genes involved in the formation, maintenance or disassembly of ciliary structures cause a wide array of developmental genetic disorders, also known as ciliopathies. The primary cilium is formed during G1 in the cell cycle and disassembles at the G2/M transition. Following the completion of the cell division, the cilium reassembles in G1. This cycle is finely regulated at multiple levels. The ubiquitin-proteasome system (UPS) and the autophagy machinery, two main protein degradative systems in cells, play a fundamental role in cilium dynamics. Evidence indicate that UPS, autophagy and signaling pathways may act in synergy to control the ciliary homeostasis. However, the mechanisms involved and the links between these regulatory systems and cilium biogenesis, dynamics and signaling are not well defined yet. Here, we discuss the reciprocal regulation of signaling pathways and proteolytic machineries in the control of the assembly and disassembly of the primary cilium, and the impact of the derangement of these regulatory networks in human ciliopathies.
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17
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Sartorius K, Antwi SO, Chuturgoon A, Roberts LR, Kramvis A. RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality? Front Oncol 2022; 12:891812. [PMID: 35600358 PMCID: PMC9115561 DOI: 10.3389/fonc.2022.891812] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/04/2022] [Indexed: 11/24/2022] Open
Abstract
Despite the early promise of RNA therapeutics as a magic bullet to modulate aberrant signaling in cancer, this field remains a work-in-progress. Nevertheless, RNA therapeutics is now a reality for the treatment of viral diseases (COVID-19) and offers great promise for cancer. This review paper specifically investigates RNAi as a therapeutic option for HCC and discusses a range of RNAi technology including anti-sense oligonucleotides (ASOs), Aptamers, small interfering RNA (siRNA), ribozymes, riboswitches and CRISPR/Cas9 technology. The use of these RNAi based interventions is specifically outlined in three primary strategies, namely, repressing angiogenesis, the suppression of cell proliferation and the promotion of apoptosis. We also discuss some of the inherent chemical and delivery problems, as well as targeting issues and immunogenic reaction to RNAi interventions.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Department of Surgery, KZN Kwazulu-Natal (UKZN) Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Samuel O. Antwi
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Lewis R. Roberts
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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18
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Target Therapy for Hepatocellular Carcinoma: Beyond Receptor Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors. BIOLOGY 2022; 11:biology11040585. [PMID: 35453784 PMCID: PMC9027240 DOI: 10.3390/biology11040585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/19/2022] [Accepted: 04/07/2022] [Indexed: 11/24/2022]
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and its incidence is steadily increasing. The development of HCC is a complex, multi-step process that is accompanied by alterations in multiple signaling cascades. Recent years have seen advancement in understanding molecular signaling pathways that play central roles in hepatocarcinogenesis. Aberrant activation of YAP/TAZ, Hedgehog, or Wnt/β-catenin signaling is frequently found in a subset of HCC patients. Targeting the signaling pathway via small molecule inhibitors could be a promising therapeutic option for the subset of patients. In this review, we will introduce the signaling pathways, discuss their roles in the development of HCC, and propose a therapeutic approach targeting the signaling pathways in the context of HCC. Abstract Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. To date, receptor tyrosine kinases (RTKs) are the most favored molecular targets for the treatment of HCC, followed by immune checkpoint regulators such as PD-1, PD-L1, and CTLA-4. With less than desirable clinical outcomes from RTK inhibitors as well as immune checkpoint inhibitors (ICI) so far, novel molecular target therapies have been proposed for HCC. In this review, we will introduce diverse molecular signaling pathways that are aberrantly activated in HCC, focusing on YAP/TAZ, Hedgehog, and Wnt/β-catenin signaling pathways, and discuss potential therapeutic strategies targeting the signaling pathways in HCC.
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19
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Zabady S, Mahran N, Soltan MA, Alaa Eldeen M, Eid RA, Albogami S, Fayad E, Matboli M, Habib EK, Hasanin AH, A. Ali M, Mesbah NM, Abo-Elmatty DM, Abdel-Hamed AR. Cyanidin-3-Glucoside Modulates hsa_circ_0001345/miRNA106b/ATG16L1 Axis Expression as a Potential Protective Mechanism against Hepatocellular Carcinoma. Curr Issues Mol Biol 2022; 44:1677-1687. [PMID: 35723373 PMCID: PMC9164082 DOI: 10.3390/cimb44040115] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/17/2022] [Accepted: 03/23/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of malignancy in the liver. Autophagy was found to have a significant effect in controlling HCC. Anthocyanins, which are naturally occurring pigments in a variety of fruits and vegetables, have been thoroughly documented to be involved in a variety of bioactive activities and are widely employed for their antioxidant capabilities. Cyanidin-3-glucoside (C3G) extracted from Morus alba L. has promising antioxidant and anti-tumour activities. The current study aims to examine the protective action of C3G against hepatocellular carcinoma through the investigation of the autophagy protein ATG16L1 expression along with its related RNA molecules (hsa_circ_0001345 and miRNA106b) in Wistar rats. In vivo precancerous lesions (PCL) were induced using diethylnitrosamine (DEN) and acetamidofluorene (2-AAF). Rats were treated with C3G (10, 15, and 20 mg/kg; 4 times weekly) for 112 days (16 weeks). Liver function tests, alfa fetoprotein, ATG16L1 expression, hsa_circ_0001345, and miRNA106b differential expression were examined. Liver sections were examined by histological and immunohistochemical approaches. The current study's findings indicated that C3G administration protects against the negative effects of DEN-2-AAF on liver functions and liver histopathological sections, which nominated C3G as a potential prophylactic agent against HCC.
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Affiliation(s)
- Shaimaa Zabady
- Department of Biochemistry, Faculty of Pharmacy, Sinai University, Ismailia 16020, Egypt;
| | - Nievin Mahran
- Department of Biochemistry, Faculty of Dentistry, Sinai University, Ismailia 16020, Egypt;
| | - Mohamed A. Soltan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Sinai University, Ismailia 16020, Egypt
| | - Muhammad Alaa Eldeen
- Cell Biology, Histology & Genetics Division, Zoology Department, Faculty of Science, Zagazig University, Alsharquia 44519, Egypt
| | - Refaat A. Eid
- Department of Pathology, College of Medicine, King Khalid University, Abha 12573, Saudi Arabia;
| | - Sarah Albogami
- Department of Biotechnology, College of Science, Taif University, Taif 21944, Saudi Arabia; (S.A.); (E.F.)
| | - Eman Fayad
- Department of Biotechnology, College of Science, Taif University, Taif 21944, Saudi Arabia; (S.A.); (E.F.)
| | - Marwa Matboli
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt;
| | - Eman K. Habib
- Faculty of Medicine, Galala University, Galala City 43511, Egypt;
- Department of Anatomy, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Amany H. Hasanin
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt;
| | - Mahmoud A. Ali
- Department of Molecular Microbiology, Faculty of Medicine, Armed Forces College, Cairo 11566, Egypt;
| | - Noha M. Mesbah
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; (N.M.M.); (D.M.A.-E.); (A.R.A.-H.)
| | - Dina M. Abo-Elmatty
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; (N.M.M.); (D.M.A.-E.); (A.R.A.-H.)
| | - Asmaa R. Abdel-Hamed
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; (N.M.M.); (D.M.A.-E.); (A.R.A.-H.)
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20
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Ravichandran R, PriyaDharshini LC, Sakthivel KM, Rasmi RR. Role and regulation of autophagy in cancer. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166400. [PMID: 35341960 DOI: 10.1016/j.bbadis.2022.166400] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 02/07/2023]
Abstract
Autophagy is an intracellular self-degradative mechanism which responds to cellular conditions like stress or starvation and plays a key role in regulating cell metabolism, energy homeostasis, starvation adaptation, development and cell death. Numerous studies have stipulated the participation of autophagy in cancer, but the role of autophagy either as tumor suppressor or tumor promoter is not clearly understood. However, mechanisms by which autophagy promotes cancer involves a diverse range of modifications of autophagy associated proteins such as ATGs, Beclin-1, mTOR, p53, KRAS etc. and autophagy pathways like mTOR, PI3K, MAPK, EGFR, HIF and NFκB. Furthermore, several researches have highlighted a context-dependent, cell type and stage-dependent regulation of autophagy in cancer. Alongside this, the interaction between tumor cells and their microenvironment including hypoxia has a great potential in modulating autophagy response in favour to substantiate cancer cell metabolism, self-proliferation and metastasis. In this review article, we highlight the mechanism of autophagy and their contribution to cancer cell proliferation and development. In addition, we discuss about tumor microenvironment interaction and their consequence on selective autophagy pathways and the involvement of autophagy in various tumor types and their therapeutic interventions concentrated on exploiting autophagy as a potential target to improve cancer therapy.
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Affiliation(s)
- Rakesh Ravichandran
- Department of Biotechnology, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore 641 014, Tamil Nadu, India
| | | | - Kunnathur Murugesan Sakthivel
- Department of Biochemistry, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore 641 014, Tamil Nadu, India
| | - Rajan Radha Rasmi
- Department of Biotechnology, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore 641 014, Tamil Nadu, India.
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21
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Onishi H, Nakamura K, Yanai K, Nagai S, Nakayama K, Oyama Y, Fujimura A, Ozono K, Yamasaki A. Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review). Oncol Rep 2022; 47:93. [DOI: 10.3892/or.2022.8304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/25/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Katsuya Nakamura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kosuke Yanai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Shuntaro Nagai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kazunori Nakayama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Yasuhiro Oyama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Akiko Fujimura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Keigo Ozono
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Akio Yamasaki
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
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22
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Understanding autophagy role in cancer stem cell development. Mol Biol Rep 2022; 49:6741-6751. [PMID: 35277787 DOI: 10.1007/s11033-022-07299-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 02/23/2022] [Indexed: 12/30/2022]
Abstract
Cancer stem cells (CSCs) are a small subpopulation of immature cells located in the tumor mass. These cells are responsible for tumor development, proliferation, resistance and spreading. CSCs are characterized by three unique features: the ability to self-renew, differentiation and tumor formation. CSCs are similar to stem cells, but they differ in the malignant phenotype. CSCs become immortal and survive harsh environmental conditions such as hypoxia, starvation and oxidative stress. However, this harsh tumor microenvironment induces the activation of autophagy, which further increases the CSCs stemness profile, and all these features further increase tumorigenicity and metastasis capacity. Autophagy is induced by the extracellular and cellular microenvironment. Hypoxia is one of the most common factors that highly increases the activity of autophagy in CSCs. Therefore, hypoxia-induced autophagy and CSCs proliferation should be elucidated in order to find a novel cure to defeat cancer cells (CSCs and non-CSCs). The remaining challenges to close the gap between the laboratory bench and the development of therapies, to use autophagy against CSCs in patients, could be addressed by adopting a 3D platform to better-mimic the natural environment in which these cells reside. Ultimately allowing to obtain the blueprints for bioprocess scaling up and to develop the production pipeline for safe and cost-effective autophagy-based novel biologics.
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23
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Zheng X, Liu X, Lei Y, Wang G, Liu M. Glypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinoma. Front Oncol 2022; 12:824208. [PMID: 35251989 PMCID: PMC8889910 DOI: 10.3389/fonc.2022.824208] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/18/2022] [Indexed: 02/05/2023] Open
Abstract
Glypican-3 (GPC3) is a membrane-associated proteoglycan that is specifically up-regulated in hepatocellular carcinoma (HCC) although rarely or not expressed in normal liver tissues, making it a perfect diagnostic and treatment target for HCC. Several GPC3-based clinical trials are ongoing and recently several innovative GPC3-targeted therapeutic methods have emerged with exciting results, including GPC3 vaccine, anti-GPC3 immunotoxin, combined therapy with immune checkpoint blockades (ICBs), and chimeric antigen receptor (CAR) T or NK cells. Here, we review the value of GPC3 in the diagnosis and prognosis of HCC, together with its signaling pathways, with a specific focus on GPC3-targeted treatments of HCC and some prospects for the future GPC3-based therapeutic strategies in HCC.
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Affiliation(s)
- Xiufeng Zheng
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Xun Liu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Yanna Lei
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Gang Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Ming Liu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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Zhang G, Xu Z, Yu M, Gao H. Bcl-2 interacting protein 3 (BNIP3) promotes tumor growth in breast cancer under hypoxic conditions through an autophagy-dependent pathway. Bioengineered 2022; 13:6280-6292. [PMID: 35200106 PMCID: PMC8973668 DOI: 10.1080/21655979.2022.2036399] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Hypoxia-induced autophagy has been implicated in many cancers. Bcl-2 interacting protein 3 (BNIP3) has been associated with hypoxia, whose aberrant expression is involved in the carcinogenesis of breast cancer (BC). Here, we aim to investigate the role of hypoxia-induced autophagy and the mechanistic actions of the bioinformatically identified BNIP3 in BC. The expression pattern of BNIP3 in BC tissues and cell lines was examined using RT-qPCR and Western blot analyses. The binding affinity among BNIP3, BECN1 and BCL-2 was characterized by co-immunoprecipitation. BNIP3 expression was manipulated to assess its effects on BC cell malignant phenotypes, evaluated by cell counting kit-8, Transwell and wound healing assays, and on BC autophagy under hypoxic conditions. A BC tumor xenografts mouse model was further established to substantiate in vitro findings. Up-regulated expression of BNIP3 was found in BC tissues and cell lines, and BNIP3 expression was positively correlated with hypoxia exposure duration. BNIP3 knockdown restricted BC cell proliferation, invasion, and migration under hypoxic conditions. BNIP3 activated BC cell autophagy by inhibiting the binding between BCL-2 and BECN1 under hypoxic conditions. BNIP3-induced autophagy activation enhanced malignant phenotypes of BC cells, thus accelerating the tumorigenesis of BC cells in vivo. These data collectively supported the tumor-promoting role of BNIP3 in autophagy activation of BC under hypoxic conditions, highlighting a potential therapeutic target against BC.
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Affiliation(s)
- Guipu Zhang
- Department of Breast Surgery, Changzhou Cancer Hospital, Changzhou, China
| | - Zhiyi Xu
- Department of Pathology, Changzhou Cancer Hospital, Changzhou, China
| | - Minjing Yu
- Department of Breast Surgery, Changzhou Cancer Hospital, Changzhou, China
| | - Haiyan Gao
- Department of Breast Surgery, Changzhou Cancer Hospital, Changzhou, China
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Zhou Y, Zhao X, Zhang L, Xia Q, Peng Y, Zhang H, Yan D, Yang Z, Li J. Iron overload inhibits cell proliferation and promotes autophagy via PARP1/SIRT1 signaling in endometriosis and adenomyosis. Toxicology 2022; 465:153050. [PMID: 34826546 DOI: 10.1016/j.tox.2021.153050] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 11/10/2021] [Accepted: 11/20/2021] [Indexed: 10/19/2022]
Abstract
Emerging evidence suggests that excess iron accumulates in endometriotic and adenomyotic lesions. However, the role iron overload plays in the pathogenesis of endometriosis or adenomyosis remains unknown. Primary human eutopic endometrial stromal cells (EuESCs) from endometriosis or adenomyosis patients were used as the in vitro model of endometriosis or adenomyosis in this study. We found that iron, manifesting as ferric ammonium citrate (FAC; 0.05-4.8 mM), significantly inhibited cell growth, induced oxidative stress through the Fenton reaction, and functionally activated autophagy in EuESCs, as measured by 5-ethynyl-2'-deoxyuridine incorporation assay, MitoSOX™ Red staining, LC3 turnover assay, and tandem mCherry-eGFP-LC3B fluorescence microscopy. Immunohistochemistry analysis of Ki67 expression in proliferative-phase endometrial tissues revealed that cell proliferation in ectopic tissues was dramatically compromised, suggesting that iron overload may play a role in cell growth inhibition in vivo. We observed that autophagy may alleviate the FAC-induced inhibition of endometrial stromal cell proliferation. Furthermore, sequential FAC (0.8 mM, 24 h) and hydrogen peroxide (H2O2; 300 μM, 2 h) treatment successfully induced the Fenton reaction in EuESCs and caused extensive apoptosis, whereas the disruption of autophagy by the knockdown of BECN1 further aggravated cell death. MitoSOX™ Red staining showed that autophagy may promote the survival of EuESCs by decreasing of the Fenton reaction-induced reactive oxygen species generation. In addition, we observed that the Fenton reaction-induced oxidative stress significantly suppressed iron overload-induced autophagy. Moreover, we found that FAC treatment impaired poly(ADP-ribose)-polymerase 1 (PARP1) expression while simultaneously upregulating SIRT1 expression in EuESCs. Our data further showed that PARP1 expression decreased in endometriotic lesions, which may partially result from iron overload. We also found that PARP1 inhibition aggravated iron overload-induced cell growth suppression, and was implicated in iron overload-induced autophagy. In addition, SIRT1 silencing alleviated iron overload-induced PARP1 downregulation and autophagy activation. Overall, our data suggest that iron overload in endometrial stromal cells of endometriotic or adenomyotic lesions may be involved in the inhibition of cell proliferation, simultaneously with the activation of protective autophagy via PARP1/SIRT1 signaling.
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Affiliation(s)
- Yingying Zhou
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Xiumin Zhao
- Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Lingmin Zhang
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Qingqing Xia
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Yangying Peng
- Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Huiping Zhang
- Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Dewen Yan
- Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
| | - Zaixing Yang
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.
| | - Jie Li
- Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.
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Zeng S, Zhou F, Wang Y, Zhai Z, Xu L, Wang H, Chen X, Luo S, Cheng M. Aberrant expression of the extracellular matrix component Biglycan regulated by Hedgehog signalling promotes colorectal cancer cell proliferation. Acta Biochim Biophys Sin (Shanghai) 2021; 54:243-251. [PMID: 35130618 PMCID: PMC9909327 DOI: 10.3724/abbs.2021018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Hedgehog (Hh) signalling plays essential roles in regulating embryonic development and contributes to tumour initiation, growth and progression in multiple cancers. The detailed mechanism by which Hh signalling participates in tumour growth warrants thorough study, although several downstream target genes have been identified. Herein, a set of novel targets of Hh signalling was identified in multiple types of tumour cells via RNA-Seq analysis. Among these targets, the expression regulation and oncogenic function of the extracellular matrix component biglycan (BGN) were investigated. Further investigation verified that Hh signalling activates the expression of BGN via the transcription factor Gli2, which directly binds to the promoter region of BGN. Functional assays revealed that BGN facilitates tumour cell growth and proliferation in colorectal cancer (CRC) cells, and xenograft assays confirmed that BGN also promotes tumour growth . Moreover, analysis of clinical CRC samples showed that both the protein and mRNA levels of BGN are increased in CRC tissues compared to those in adjacent tissues, and higher expression of BGN is correlated with poorer prognosis of CRC patients, further confirming the function of BGN in CRC. Taken together, aberrantly activated Hh signalling increases the expression of BGN, possibly regulates the extracellular matrix, and thereby promotes tumour growth in CRC.
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Affiliation(s)
- Shaopeng Zeng
- Center for Experimental Medicinethe First Affiliated Hospital of Nanchang UniversityNanchang330006China,Jiangxi Key Laboratory of Molecular Diagnostics and Precision MedicineNanchang330006China
| | - Feifei Zhou
- Center for Experimental Medicinethe First Affiliated Hospital of Nanchang UniversityNanchang330006China,Jiangxi Key Laboratory of Molecular Diagnostics and Precision MedicineNanchang330006China,School of Basic Medical SciencesNanchang UniversityNanchang330006China
| | - Yiqing Wang
- Center for Experimental Medicinethe First Affiliated Hospital of Nanchang UniversityNanchang330006China,Jiangxi Key Laboratory of Molecular Diagnostics and Precision MedicineNanchang330006China
| | - Zhenyu Zhai
- Center for Experimental Medicinethe First Affiliated Hospital of Nanchang UniversityNanchang330006China,Jiangxi Key Laboratory of Molecular Diagnostics and Precision MedicineNanchang330006China
| | - Linlin Xu
- Center for Experimental Medicinethe First Affiliated Hospital of Nanchang UniversityNanchang330006China,Jiangxi Key Laboratory of Molecular Diagnostics and Precision MedicineNanchang330006China
| | - Hailong Wang
- Center for Experimental Medicinethe First Affiliated Hospital of Nanchang UniversityNanchang330006China,Jiangxi Key Laboratory of Molecular Diagnostics and Precision MedicineNanchang330006China
| | - Xinping Chen
- Department of Obstetrics & Gynecologythe First Affiliated Hospital of Nanchang UniversityNanchang330006China
| | - Shiwen Luo
- Center for Experimental Medicinethe First Affiliated Hospital of Nanchang UniversityNanchang330006China,Jiangxi Key Laboratory of Molecular Diagnostics and Precision MedicineNanchang330006China
| | - Minzhang Cheng
- Center for Experimental Medicinethe First Affiliated Hospital of Nanchang UniversityNanchang330006China,Jiangxi Key Laboratory of Molecular Diagnostics and Precision MedicineNanchang330006China,Correspondence address. Tel: +86-791-88692139; E-mail:
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Zheng J, Cheng C, Xu J, Gao P, Wang J, Chen L. miR-142-3p Regulates Tumor Cell Autophagy and Promotes Colon Cancer Progression by Targeting TP53INP2. Chemotherapy 2021; 67:57-66. [PMID: 34753133 DOI: 10.1159/000520750] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 11/05/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Colon cancer (CC) is the third largest cancer worldwide. Investigation of the molecular mechanism of CC progression helps to explore novel therapeutic targets. We attempted to understand the modulatory mechanism of miR-142-3p in CC cell autophagy and CC progression, which will lay a theoretical groundwork for seeking potential diagnostic and therapeutic targets for CC. METHODS Through bioinformatics methods, miRNA expression data were subjected to differential analysis for identification of target miRNA. Downstream target mRNAs were predicted and gene set enrichment analysis (GSEA) was completed. qRT-PCR assessed gene expression in cells. Cell Counting Kit-8, cell doubling time calculation, colony formation, and flow cytometry were used to assess cellular biological functions. Dual-luciferase assay was used for targeting relationship validation of the target miRNA and mRNA. Western blot was performed to evaluate expression of proteins related to HEDGEHOG signaling pathway and autophagy. RESULTS miR-142-3p was markedly highly expressed in CC, and high miR-142-3p expression in CC patients was implicated with relatively poor prognosis. Over-expressing miR-142-3p facilitated proliferation and inhibited apoptosis of CC cells, whereas silencing it produced an opposite result. miR-142-3p targeted and decreased TP53INP2 level. TP53INP2 over-expression suppressed the HEDGEHOG signaling pathway and induced the activation of CC cell autophagy. Rescue experiments revealed that influence of miR-142-3p inhibitor on CC cell proliferation and apoptosis could be reversed by silencing TP53INP2. CONCLUSION miR-142-3p hampered tumor cell autophagy and promoted CC progression via targeting TP53INP2, which will offer a fresh research orientation for the diagnosis of CC.
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Affiliation(s)
- Jiujian Zheng
- Department of Colorectal and Anal Surgery, Lishui Municipal Central Hospital, Lishui, China
| | - Chuan Cheng
- Department of Colorectal and Anal Surgery, Lishui Municipal Central Hospital, Lishui, China
| | - Jie Xu
- Department of Colorectal and Anal Surgery, Lishui Municipal Central Hospital, Lishui, China
| | - Peng Gao
- Department of Colorectal and Anal Surgery, Lishui Municipal Central Hospital, Lishui, China
| | - Jianping Wang
- Department of Colorectal and Anal Surgery, Lishui Municipal Central Hospital, Lishui, China
| | - Lifei Chen
- Department of Colorectal and Anal Surgery, Lishui Municipal Central Hospital, Lishui, China
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Qiao L, Liu X, He Y, Zhang J, Huang H, Bian W, Chilufya MM, Zhao Y, Han J. Progress of Signaling Pathways, Stress Pathways and Epigenetics in the Pathogenesis of Skeletal Fluorosis. Int J Mol Sci 2021; 22:ijms222111932. [PMID: 34769367 PMCID: PMC8584317 DOI: 10.3390/ijms222111932] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022] Open
Abstract
Fluorine is widely dispersed in nature and has multiple physiological functions. Although it is usually regarded as an essential trace element for humans, this view is not held universally. Moreover, chronic fluorosis, mainly characterized by skeletal fluorosis, can be induced by long-term excessive fluoride consumption. High concentrations of fluoride in the environment and drinking water are major causes, and patients with skeletal fluorosis mainly present with symptoms of osteosclerosis, osteochondrosis, osteoporosis, and degenerative changes in joint cartilage. Etiologies for skeletal fluorosis have been established, but the specific pathogenesis is inconclusive. Currently, active osteogenesis and accelerated bone turnover are considered critical processes in the progression of skeletal fluorosis. In recent years, researchers have conducted extensive studies in fields of signaling pathways (Wnt/β-catenin, Notch, PI3K/Akt/mTOR, Hedgehog, parathyroid hormone, and insulin signaling pathways), stress pathways (oxidative stress and endoplasmic reticulum stress pathways), epigenetics (DNA methylation and non-coding RNAs), and their inter-regulation involved in the pathogenesis of skeletal fluorosis. In this review, we summarised and analyzed relevant findings to provide a basis for comprehensive understandings of the pathogenesis of skeletal fluorosis and hopefully propose more effective prevention and therapeutic strategies.
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29
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Ping F, Zhang C, Wang X, Wang Y, Zhou D, Hu J, Chen Y, Ling J, Zhou J. Cx32 inhibits the autophagic effect of Nur77 in SH-SY5Y cells and rat brain with ischemic stroke. Aging (Albany NY) 2021; 13:22188-22207. [PMID: 34551394 PMCID: PMC8507301 DOI: 10.18632/aging.203526] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 09/02/2021] [Indexed: 12/15/2022]
Abstract
The pathogenesis of cerebral ischemia-reperfusion (I/R) is complex. Cx32 expression has been reported to be up-regulated in ischemic lesions of aged human brain. Nevertheless, the function of Cx32 during cerebral I/R is poorly understood. Autophagy is of vital importance in the pathogenesis of cerebral I/R. In the current study, we found that oxygen-glucose deprivation/reoxygenation (OGD/R) or I/R insult significantly induced the up-regulation of Cx32 and activation of autophagy. Inhibition of Cx32 alleviated OGD/R or I/R injury, and further activated autophagy. In addition, Nur77 expression was found to be up-regulated after OGD/R or I/R. After inhibiting Cx32, the expression of Nur77 was further increased and Nur77 was translocated from nucleus to mitochondrial. Inhibition of Cx32 also activated mitophagy by promoting autophagosome formation and up-regulating the expression of mitochondrial autophagy marker molecules. Of note, in the siNur77-transfected cells, the number of dysfunctional mitochondrial was increased, and mitophagy was suppressed, which aggravated OGD/R-induced neuronal injury. In conclusion, Cx32 might act as a regulatory factor of Nur77 controlling neuronal autophagy in the brains. Understanding the mechanism of this regulatory pathway will provide new insight into the role Cx32 and Nur77 in cerebral ischemia, offering new opportunities for therapeutics.
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Affiliation(s)
- Fengfeng Ping
- Department of Reproductive Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China
| | - Chao Zhang
- Department of Reproductive Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214023, China
| | - Xue Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Yan Wang
- Department of Good Clinical Practice, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi 214023, China
| | - Danli Zhou
- Department of Good Clinical Practice, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi 214023, China
| | - Jing Hu
- Department of Good Clinical Practice, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi 214023, China
| | - Yanhua Chen
- Department of Good Clinical Practice, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi 214023, China
| | - Jingjing Ling
- Department of Good Clinical Practice, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi 214023, China
| | - Jia Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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Sun J, Lin W, Li C, Ueki H, Xue R, Sadahira T, Hu H, Wada K, Li N, Liu C, Araki M, Xu A, Huang P. Repurposing of posaconazole as a hedgehog/SMO signaling inhibitor for embryonal rhabdomyosarcoma therapy. Am J Cancer Res 2021; 11:4528-4540. [PMID: 34659903 PMCID: PMC8493378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/16/2021] [Indexed: 06/13/2023] Open
Abstract
Posaconazole (POS) is a novel antifungal agent, which has been repurposed as an anti-tumor drug for its potential inhibition of Hedgehog signaling pathway. Hedgehog pathway is reported to be abnormally activated in embryonal rhabdomyosarcoma (ERMS), this study aimed to reveal whether POS could inhibit Hedgehog signaling pathway in ERMS. Following POS treatment, XTT viability assay was used to determine the cell proliferation of ERMS cell lines. Protein changes related to Hedgehog signaling, cell cycle and autophagy were detected by Western blot. The cell cycle distribution was analyzed by flow cytometry. Moreover, a subcutaneous tumor mouse model of ERMS was established to assess the anti-tumor effect of POS. POS was found to inhibit tumor progression by inducing G0/G1 arrest and autophagy of RD, RMS-YM, and KYM-1 cells dose-dependently. Western blot demonstrated that POS downregulated the expressions of SMO, Gli1, c-Myc, CDK4, and CDK6, while upregulated the expressions of autophagy-related proteins. Immunofluorescence microscopy revealed a significant increase of LC3B puncta in POS-treated ERMS cells. Furthermore, POS treatment led to a significant inhibition of tumor growth in mice bearing ERMS. Our findings could provide a theoretical basis and have important clinical implications in developing POS as a promising agent against ERMS by targeting Hedgehog pathway.
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Affiliation(s)
- Jingkai Sun
- Department of Urology, Zhujiang Hospital, Southern Medical UniversityGuangzhou, China
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Wenfeng Lin
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Chaoming Li
- Department of Urology, Zhujiang Hospital, Southern Medical UniversityGuangzhou, China
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Hideo Ueki
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Ruizhi Xue
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Takuya Sadahira
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Hao Hu
- Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityGuangzhou, China
| | - Koichiro Wada
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Na Li
- Laboratory of Medical Systems Biology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityGuangzhou, China
| | - Chunxiao Liu
- Department of Urology, Zhujiang Hospital, Southern Medical UniversityGuangzhou, China
| | - Motoo Araki
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
| | - Abai Xu
- Department of Urology, Zhujiang Hospital, Southern Medical UniversityGuangzhou, China
| | - Peng Huang
- Department of Urology, Zhujiang Hospital, Southern Medical UniversityGuangzhou, China
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama, Japan
- Okayama Medical Innovation Center, Okayama UniversityOkayama, Japan
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Bousali M, Papatheodoridis G, Paraskevis D, Karamitros T. Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma. Microorganisms 2021; 9:1787. [PMID: 34442866 PMCID: PMC8398950 DOI: 10.3390/microorganisms9081787] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal-fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO's commitment to eliminate HBV and viral hepatitis by 2030.
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Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - George Papatheodoridis
- Department of Gastroenterology, “Laiko” General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Paraskevis
- Department of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
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Carballo GB, Ribeiro JH, Lopes GPDF, Ferrer VP, Dezonne RS, Pereira CM, Spohr TCLDSE. GANT-61 Induces Autophagy and Apoptosis in Glioblastoma Cells despite their heterogeneity. Cell Mol Neurobiol 2021; 41:1227-1244. [PMID: 32504326 PMCID: PMC11448572 DOI: 10.1007/s10571-020-00891-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 05/28/2020] [Indexed: 12/24/2022]
Abstract
Glioblastoma (GBM) is the most common adult primary tumor of the CNS characterized by rapid growth and diffuse invasiveness into the brain parenchyma. The GBM resistance to chemotherapeutic drugs may be due to the presence of cancer stem cells (CSCs). The CSCs activate the same molecular pathways as healthy stem cells such as WNT, Sonic hedgehog (SHH), and Notch. Mutations or deregulations of those pathways play a key role in the proliferation and differentiation of their surrounding environment, leading to tumorigenesis. Here we investigated the effect of SHH signaling pathway inhibition in human GBM cells by using GANT-61, considering stem cell phenotype, cell proliferation, and cell death. Our results demonstrated that GANT-61 induces apoptosis and autophagy in GBM cells, by increasing the expression of LC3 II and cleaved caspase 3 and 9. Moreover, we observed that SHH signaling plays a crucial role in CSC phenotype maintenance, being also involved in the epithelial-mesenchymal transition (EMT) phenotype. We also noted that SHH pathway modulation can regulate cell proliferation as revealed through the analysis of Ki-67 and c-MYC expressions. We concluded that SHH signaling pathway inhibition may be a promising therapeutic approach to treat patients suffering from GBM refractory to traditional treatments.
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Affiliation(s)
- Gabriela Basile Carballo
- Instituto Estadual Do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro, RJ, 20231-092, Brazil
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
- Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, University of Zurich, Zurich, Switzerland
| | - Jessica Honorato Ribeiro
- Instituto Estadual Do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro, RJ, 20231-092, Brazil
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
- Radiobiology Unit, Belgian Nuclear Research Centre, SCK·CEN, Mol, Belgium
| | - Giselle Pinto de Faria Lopes
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
- Departamento de Biotecnologia Marinha, Instituto de Estudos do Mar Almirante Paulo Moreira (IEAPM)/Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil
| | - Valéria Pereira Ferrer
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
- Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niteroi, Rio de Janeiro, Brazil
| | - Romulo Sperduto Dezonne
- Programa de Pós-Graduação em Biomedicina Translacional, Universidade Do Grande Rio, Duque de Caxias, Brazil
| | - Cláudia Maria Pereira
- Programa de Pós-Graduação em Biomedicina Translacional, Universidade Do Grande Rio, Duque de Caxias, Brazil
| | - Tania Cristina Leite de Sampaio E Spohr
- Instituto Estadual Do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro, RJ, 20231-092, Brazil.
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.
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Mir IH, Guha S, Behera J, Thirunavukkarasu C. Targeting molecular signal transduction pathways in hepatocellular carcinoma and its implications for cancer therapy. Cell Biol Int 2021; 45:2161-2177. [PMID: 34270844 DOI: 10.1002/cbin.11670] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/22/2021] [Accepted: 07/11/2021] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma is a substantial health concern. It is currently the third dominating cause of mortality associated with cancer worldwide. The development of hepatocellular carcinoma is an intricate process that encompasses the impairment of genetic, epigenetic, and signal transduction mechanisms contributing to an aberrant metabolic system, enabling tumorigenesis. Throughout the past decade, research has led to the revelation of molecular pathways implicated in the progression of this notorious disorder. The altered signal transduction pathways, such as the mitogen-activated protein kinase pathway, phosphoinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, WNT/β-catenin pathway, hepatocyte growth factor/c-MET pathway, and just another kinase/signal transducers and activators of transcription signaling pathway is of much therapeutic significance, as targeting them may avail to revert, retard or avert hepatocarcinogenesis. The present review article sums up the contemporary knowledge of such signaling mechanisms, including their therapeutic targets and betokens that novel and efficacious therapies can be developed only by the keen understanding of their character in hepatocarcinogenesis. In additament, we address the role of consequential therapeutic agents and preclinical nondrug therapies known for combating hepatocarcinogenesis.
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Affiliation(s)
- Ishfaq Hassan Mir
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
| | - Shreyoshi Guha
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
| | - Jajnasenee Behera
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
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Wei Y, Sun H, Gui T, Yao L, Zhong L, Yu W, Heo SJ, Han L, Dyment NA, Liu XS, Zhang Y, Koyama E, Long F, Zgonis MH, Mauck RL, Ahn J, Qin L. The critical role of Hedgehog-responsive mesenchymal progenitors in meniscus development and injury repair. eLife 2021; 10:e62917. [PMID: 34085927 PMCID: PMC8177886 DOI: 10.7554/elife.62917] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 05/18/2021] [Indexed: 12/18/2022] Open
Abstract
Meniscal tears are associated with a high risk of osteoarthritis but currently have no disease-modifying therapies. Using a Gli1 reporter line, we found that Gli1+ cells contribute to the development of meniscus horns from 2 weeks of age. In adult mice, Gli1+ cells resided at the superficial layer of meniscus and expressed known mesenchymal progenitor markers. In culture, meniscal Gli1+ cells possessed high progenitor activities under the control of Hh signal. Meniscus injury at the anterior horn induced a quick expansion of Gli1-lineage cells. Normally, meniscal tissue healed slowly, leading to cartilage degeneration. Ablation of Gli1+ cells further hindered this repair process. Strikingly, intra-articular injection of Gli1+ meniscal cells or an Hh agonist right after injury accelerated the bridging of the interrupted ends and attenuated signs of osteoarthritis. Taken together, our work identified a novel progenitor population in meniscus and proposes a new treatment for repairing injured meniscus and preventing osteoarthritis.
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MESH Headings
- Animals
- Cell Lineage
- Cell Proliferation
- Disease Models, Animal
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Humans
- Male
- Menisci, Tibial/metabolism
- Menisci, Tibial/pathology
- Menisci, Tibial/surgery
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells/metabolism
- Mice, Knockout
- Osteoarthritis, Knee/genetics
- Osteoarthritis, Knee/metabolism
- Osteoarthritis, Knee/pathology
- Osteoarthritis, Knee/prevention & control
- Signal Transduction
- Swine
- Swine, Miniature
- Tibial Meniscus Injuries/genetics
- Tibial Meniscus Injuries/metabolism
- Tibial Meniscus Injuries/pathology
- Tibial Meniscus Injuries/surgery
- Time Factors
- Wound Healing
- Zinc Finger Protein GLI1/genetics
- Zinc Finger Protein GLI1/metabolism
- Mice
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Affiliation(s)
- Yulong Wei
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Hao Sun
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhouChina
| | - Tao Gui
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan UniversityGuangzhouChina
| | - Lutian Yao
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Leilei Zhong
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Wei Yu
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Su-Jin Heo
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaUnited States
| | - Lin Han
- School of Biomedical Engineering, Science and Health Systems, Drexel UniversityPhiladelphiaUnited States
| | - Nathaniel A Dyment
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Xiaowei Sherry Liu
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Yejia Zhang
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaUnited States
- Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Eiki Koyama
- Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Fanxin Long
- Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Miltiadis H Zgonis
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Robert L Mauck
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaUnited States
| | - Jaimo Ahn
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Orthopaedic Surgery, University of Michigan Medical SchoolAnn ArborUnited States
| | - Ling Qin
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
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Pan Y, Zhou J, Zhang W, Yan L, Lu M, Dai Y, Zhou H, Zhang S, Yang J. The Sonic Hedgehog signaling pathway regulates autophagy and migration in ovarian cancer. Cancer Med 2021; 10:4510-4521. [PMID: 34076346 PMCID: PMC8267163 DOI: 10.1002/cam4.4018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 04/08/2021] [Accepted: 04/17/2021] [Indexed: 12/19/2022] Open
Abstract
Background The Sonic Hedgehog (SHH) signaling pathway plays an important role in various types of human cancers including ovarian cancer; however, its function and underlying mechanism in ovarian cancer are still not entirely understood. Methods We detected the expressions of SHH and SQSTM1 in borderline ovarian tumor tissues, epithelial ovarian cancer (EOC) tissues and benign ovarian tumor tissues. Cyclopamine (Cyp, a well‐known inhibitor of SHH signaling pathway) and chloroquine (CQ, the pharmaceutical inhibitor of autophagy) were used in vivo and in vitro (autophagic flux, CCK‐8 assay, wound healing assay, transwell assay, tumor xenograft model). The mechanism of action was explored through Quantitative RT‐PCR and Western Blot. Results We found up‐regulation of SHH and accumulation of SQSTM1/P62 in epithelial ovarian cancer. Cyp induced autophagy through the PI3K/AKT signaling pathway. Moreover, low‐dose Cyp and chloroquine (CQ) significantly promoted the migratory ability of SKOV3 cells. Conclusions Our findings suggest that inhibition of the SHH pathway and autophagy may be a potential and effective therapy for the treatment of ovarian cancer.
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Affiliation(s)
- Yibin Pan
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiena Zhou
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Yaojiang Township Central Hospital, Zhuji City, Zhejiang Province, China
| | - Weidan Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Taizhou Hospital of Zhejiang Province, Zhejiang University, Taizhou City, Zhejiang Province, China
| | - Lili Yan
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Beilun district hospital of traditional Chinese medicine, Ningbo city, Zhejiang Province, China
| | - Meifei Lu
- Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, China
| | - Yongdong Dai
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Hanjing Zhou
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Songying Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianhua Yang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
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Yang DY, Zhou X, Liu ZW, Xu XQ, Liu C. LncRNA NEAT1 accelerates renal tubular epithelial cell damage by modulating mitophagy via miR-150-5p-DRP1 axis in diabetic nephropathy. Exp Physiol 2021; 106:1631-1642. [PMID: 33914383 DOI: 10.1113/ep089547] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/26/2021] [Indexed: 12/24/2022]
Abstract
NEW FINDINGS What is the central question of this study? Diabetic nephropathy (DN) is a severe complication of diabetes correlated with a higher mortality rate in diabetic patients. Renal tubular injury participates in the pathogenesis of DN. We aimed to uncover the biological function of the NEAT1-miR-150-5p-DRP1 axis in an in vitro model of DN and elaborate the potential mechanisms. What is the main finding and its importance? NEAT1 facilitated high glucose-induced damage in HK-2 cells by reducing mitophagy via the miR-150-5p-DRP1 axis, which sheds light on DN pathogenesis and reveals a potential treatment for DN. ABSTRACT Diabetic nephropathy (DN) is a severe complication in diabetic patients, with a high mortality rate. Renal tubular injury is involved in the pathogenesis of DN. In this study, we aimed to uncover the regulatory roles of the NEAT1-miR-150-5p-DRP1 axis in an in vitro model of DN and its possible mechanisms. High glucose-challenged HK-2 cells were used as an in vitro DN model. NEAT1, miR-150-5p and DRP1 levels were assessed by RT-qPCR. Cell viability was determined by the MTT assay. MitoSOX Red and JC-1 were used to evaluate intracellular production of reactive oxygen species and mitochondrial membrane potential, respectively. Lactate dehydrogenase release and superoxide dismutase activity were assessed with commercial kits. The protein levels of DRP1, p62, BECN1(beclin 1) and BNIP3 were determined by western blotting. The interaction between NEAT1 (DRP1) and miR-150-5p was verified by a dual-luciferase reporter assay and an RNA immunoprecipitation assay. Our results showed that in response to high glucose the NEAT1 and DRP1 levels were upregulated, whereas the miR-150-5p level was downregulated in HK-2 cells. Knockdown of NEAT1 or DRP1 in high glucose-challenged HK-2 cells inhibited excessive reactive oxygen species production and lactate dehydrogenase release, increased cell viability, mitochondrial membrane potential and superoxide dismutase activity and enhanced mitophagy. Inhibition of miR-150-5p resulted in the opposite results. Mechanistically, NEAT1 sponged miR-150-5p to increase the DRP1 level. Moreover, silencing of NEAT1 or DRP1 could counteract miR-150-5p inhibition-induced deleterious effects. Collectively, our findings indicate that NEAT1 facilitates high glucose-induced damage in HK-2 cells by suppressing mitophagy via the miR-150-5p-DRP 1 axis, which sheds light on a novel mechanism of DN.
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Affiliation(s)
- Dan-Yi Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China.,Hunan Key Laboratory of Kidney Disease and Blood, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China
| | - Xiang Zhou
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China.,Hunan Key Laboratory of Kidney Disease and Blood, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China
| | - Zhi-Wen Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China.,Hunan Key Laboratory of Kidney Disease and Blood, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China
| | - Xiang-Qing Xu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China.,Hunan Key Laboratory of Kidney Disease and Blood, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China
| | - Chan Liu
- International Medical Department, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China
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Inhibition of the sonic hedgehog pathway activates TGF-β-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells. Cell Death Dis 2021; 12:459. [PMID: 33966040 PMCID: PMC8106679 DOI: 10.1038/s41419-021-03744-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 02/03/2023]
Abstract
The sonic hedgehog (Shh) pathway is highly activated in a variety of malignancies and plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. Our recent study showed that the inhibitors of the Shh pathway such as cyclopamine (CP), a Smothened (SMO) inhibitor, and GANT61, a Gli1 inhibitor, have modest inhibitory effects on thyroid tumor cell proliferation and tumor growth. The objective of this study was to determine whether autophagy was induced by inhibition of the Shh pathway and could negatively regulate GANT61-induced apoptosis. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 induced autophagy in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines; whereas Gli1 overexpression suppressed autophagy. Mechanistic investigation revealed that inhibition of the Shh pathway activated TAK1 and its two downstream kinases, the c-Jun-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). GANT61-induced autophagy was blocked by TAK1 siRNA and the inhibitors of TAK1 (5Z-7-oxozeaenol, 5Z), JNK (SP600125), and AMPK (Compound C, CC). Inhibition of autophagy by chloroquine and 5Z and by TAK1 and Beclin-1 siRNA enhanced GANT61-induced apoptosis and its antiproliferative activity. Our study has shown that inhibition of the Shh pathway induces autophagy by activating TAK1, whereas autophagy in turn suppresses GANT61-induced apoptosis. We have uncovered a previously unrecognized role of TAK1 in Shh pathway inhibition-induced autophagy and apoptosis.
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Farzaneh Z, Vosough M, Agarwal T, Farzaneh M. Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches. Cancer Cell Int 2021; 21:208. [PMID: 33849569 PMCID: PMC8045321 DOI: 10.1186/s12935-021-01924-w] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of death due to cancer. Although there are different treatment options, these strategies are not efficient in terms of restricting the tumor cell's proliferation and metastasis. The liver tumor microenvironment contains the non-parenchymal cells with supportive or inhibitory effects on the cancerous phenotype of HCC. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of liver carcinoma cells. Recent studies have established new approaches for the prevention and treatment of HCC using small molecules. Small molecules are compounds with a low molecular weight that usually inhibit the specific targets in signal transduction pathways. These components can induce cell cycle arrest, apoptosis, block metastasis, and tumor growth. Devising strategies for simultaneously targeting HCC and the non-parenchymal population of the tumor could lead to more relevant research outcomes. These strategies may open new avenues for the treatment of HCC with minimal cytotoxic effects on healthy cells. This study provides the latest findings on critical signaling pathways governing HCC behavior and using small molecules in the control of HCC both in vitro and in vivo models.
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Affiliation(s)
- Zahra Farzaneh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Tarun Agarwal
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Lu G, Wu Z, Shang J, Xie Z, Chen C, Zhang C. The effects of metformin on autophagy. Biomed Pharmacother 2021; 137:111286. [PMID: 33524789 DOI: 10.1016/j.biopha.2021.111286] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 12/11/2022] Open
Abstract
Metformin is the first-line option for treating newly diagnosed diabetic patients and also involved in other pharmacological actions, including antitumor effect, anti-aging effect, polycystic ovarian syndrome prevention, cardiovascular action, and neuroprotective effect, etc. However, the mechanisms of metformin actions were not fully illuminated. Recently, increasing researches showed that autophagy is a vital medium of metformin playing pharmacological actions. Nevertheless, results on the effects of metformin on autophagy were inconsistent. Apart from few clinical evidences, more data focused on kinds of no-clinical models. First, many studies showed that metformin could induce autophagy via a number of signaling pathways, including AMPK-related signaling pathways (e.g. AMPK/mTOR, AMPK/CEBPD, MiTF/TFE, AMPK/ULK1, and AMPK/miR-221), Redd1/mTOR, STAT, SIRT, Na+/H+ exchangers, MAPK/ERK, PK2/PKR/AKT/ GSK3β, and TRIB3. Secondly, some signaling pathways were involved in the process of metformin inhibiting autophagy, such as AMPK-related signaling pathways (AMPK/NF-κB and other undetermined AMPK-related signaling pathways), Hedgehog, miR-570-3p, miR-142-3p, and MiR-3127-5p. Thirdly, two types of signaling pathways including PI3K/AKT/mTOR and endoplasmic reticulum (ER) stress could bidirectionally impact the effectiveness of metformin on autophagy. Finally, multiple signal pathways were reviewed collectively in terms of affecting the effectiveness of metformin on autophagy. The pharmacological effects of metformin combining its actions on autophagy were also discussed. It would help better apply metformin to treat diseases in term of mediating autophagy.
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Affiliation(s)
- Guangli Lu
- School of Business, Henan University, Henan, Kaifeng, China
| | - Zhen Wu
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Henan, Kaifeng, China
| | - Jia Shang
- School of Kaifeng Culture and Tourism, Henan, Kaifeng, China
| | - Zhenxing Xie
- School of Basic Medicine, Henan University, Henan, Kaifeng, Jinming Avenue, 475004, China.
| | - Chaoran Chen
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Henan, Kaifeng, China.
| | - Chuning Zhang
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Henan, Kaifeng, China
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40
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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Pan Y, Yan L, Chen Q, Wei C, Dai Y, Tong X, Zhu H, Lu M, Zhang Y, Jin X, Zhang T, Lin X, Zhou F, Zhang S. Dysfunction of Shh signaling activates autophagy to inhibit trophoblast motility in recurrent miscarriage. Exp Mol Med 2021; 53:52-66. [PMID: 33390589 PMCID: PMC8080798 DOI: 10.1038/s12276-020-00530-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 09/23/2020] [Accepted: 10/20/2020] [Indexed: 01/29/2023] Open
Abstract
In early pregnancy, the placenta anchors the conceptus and supports embryonic development and survival. This study aimed to investigate the underlying functions of Shh signaling in recurrent miscarriage (RM), a serious disorder of pregnancy. In the present study, Shh and Gli2 were mainly observed in cytotrophoblasts (CTBs), Ptch was mainly observed in syncytiotrophoblasts (STBs), and Smo and Gli3 were expressed in both CTBs and STBs. Shh signaling was significantly impaired in human placenta tissue from recurrent miscarriage patients compared to that of gestational age-matched normal controls. VEGF-A and CD31 protein levels were also significantly decreased in recurrent miscarriage patients. Furthermore, inhibition of Shh signaling impaired the motility of JAR cells by regulating the expression of Gli2 and Gli3. Intriguingly, inhibition of Shh signaling also triggered autophagy and autolysosome accumulation. Additionally, knockdown of BECN1 reversed Gant61-induced motility inhibition. In conclusion, our results showed that dysfunction of Shh signaling activated autophagy to inhibit trophoblast motility, which suggests the Shh pathway and autophagy as potential targets for RM therapy.
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Affiliation(s)
- Yibin Pan
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Lili Yan
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China ,Beilun District Hospital of Traditional Chinese Medicine, Ningbo City, Zhejiang China
| | - Qiaoqiao Chen
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Cheng Wei
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Yongdong Dai
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Xiaomei Tong
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Haiyan Zhu
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Meifei Lu
- grid.13402.340000 0004 1759 700XDepartment of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanling Zhang
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Xiaoying Jin
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Tai Zhang
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Xiaona Lin
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Feng Zhou
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Songying Zhang
- grid.13402.340000 0004 1759 700XAssisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China ,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
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Hu Z, Xie F, Hu A, Xu M, Liu Y, Zhang J, Xiao J, Song Y, Zhong J, Chen B. Silencing glioma-associated oncogene homolog 1 suppresses the migration and invasion of hepatocellular carcinoma in vitro. Oncol Lett 2020; 20:228. [PMID: 32968450 PMCID: PMC7500057 DOI: 10.3892/ol.2020.12091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 08/20/2020] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-associated death worldwide. Glioma-associated oncogene homolog 1 (Gli1) is a key component and functions as a reliable marker of Hedgehog signaling pathway activation. Previous studies have demonstrated that Gli1 serves important roles in the progression of various types of cancer, including HCC. However, its effect on HCC invasion and metastasis and the underlying mechanism remain to be elucidated. Small interference RNA was employed to silence the Gli1 gene in liver cancer cells. Reverse transcription-quantitative PCR and western blot analysis were performed to evaluate the mRNA and protein expression of Gli1, respectively. A series of assays, including Cell Counting Kit-8, adhesion, wound healing and Matrigel invasion were performed to investigate cell viability, adhesive, migratory and invasive capabilities of liver cancer cells, respectively. In addition, immunofluorescence staining was performed to determine the cellular localization of focal adhesion kinase (FAK), phosphorylated (p-)FAK and p-AKT. The mRNA and protein expression of Gli1 in liver cancer cells (HepG2 and SK-Hep1) were markedly decreased in a dose-dependent manner following Gli1-knockdown. Gli1 silencing significantly inhibited the adhesion, migration and invasion of SK-Hep1 cells. Additionally, knockdown of Gli1 markedly suppressed the expression of metalloproteinase (MMP)-2 and MMP-9. Furthermore, downregulation of Gli1 blocked the FAK/AKT signaling pathway. Gli1 serves significant roles in the migration and invasion of HCC cells through activation of the FAK/AKT signaling pathway and subsequent upregulation of MMP-2 and MMP-9 expression. Thus, Gli1 may be a potential protein target for the regulation of HCC migration and invasion.
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Affiliation(s)
- Zeming Hu
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Fangfang Xie
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Ang Hu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Mengjing Xu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Yuwen Liu
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Jiankang Zhang
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Jianbo Xiao
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Yunlei Song
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Jianing Zhong
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Bin Chen
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
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Chen J, Wen B, Wang Y, Wu S, Zhang X, Gu Y, Wang Z, Wang J, Zhang W, Yong J. Jervine exhibits anticancer effects on nasopharyngeal carcinoma through promoting autophagic apoptosis via the blockage of Hedgehog signaling. Biomed Pharmacother 2020; 132:110898. [PMID: 33113432 DOI: 10.1016/j.biopha.2020.110898] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/09/2020] [Accepted: 10/14/2020] [Indexed: 12/30/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the superior mucosal epithelium of the nasopharynx. However, effective therapies for NPC are still required. Reducing Hedgehog signaling pathway has been shown to suppress tumor growth. In this study, we attempted to explore whether Jervine (JV), an inhibitor of Hedgehog signaling, had anti-cancer effects on NPC, and the underlying mechanisms. Our findings showed that JV treatments markedly reduced the proliferation of NPC cells in a dose- and time-dependent manner. Cell cycle arrest in G2/M phase was significantly enhanced by JV, along with evident DNA damage. Moreover, JV treatment effectively induced apoptosis in NPC cells through improving Caspase-3 activation. Furthermore, ROS production and mitochondrial impairments were detected in JV-incubated NPC cells with elevated releases of Cyto-c from mitochondria. JV also dramatically triggered autophagy through blocking AKT/mTOR and increasing AMPK signaling pathways. Intriguingly, we showed that JV-induced apoptosis was mainly via an autophagy-dependent manner. In addition, the expression levels of SHH, PTCH1, SMO and GLI1 were markedly suppressed in NPC cells, demonstrating the hindered Hedgehog signaling. Importantly, we found that JV-induced apoptosis and autophagy were closely associated with the blockage of Hedgehog signaling. Our in vivo studies confirmed the anti-cancer effects of JV on NPC through inducing autophagy, as evidenced by the markedly reduced tumor growth rate and weight without side effects and toxicity. Taken together, JV may be a promising and effective agent for human NPC treatment through repressing Hedgehog signaling pathway and inducing autophagic cell death.
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Affiliation(s)
- Jing Chen
- Department of Pathology, Jingjiang People's Hospital, Jingjiang, Jiangsu, 214500, China
| | - Bin Wen
- Department of Oncology, Jingjiang Chinese Medicine Hospital, Jingjiang, Jiangsu, 214500, China
| | - Yu Wang
- Department of Pathology, Jingjiang People's Hospital, Jingjiang, Jiangsu, 214500, China
| | - Sheng Wu
- Department of Pathology, Jingjiang People's Hospital, Jingjiang, Jiangsu, 214500, China
| | - Xuesong Zhang
- Central Laboratory, Jingjiang People's Hospital, Jingjiang, Jiangsu, 214500, China
| | - Yonggui Gu
- Department of Otolaryngology, Jingjiang People's Hospital, Jingjiang, Jiangsu, 214500, China
| | - Zhiyi Wang
- Department of Otolaryngology, East Theater General Hospital of PLA, Nanjing, Jiangsu, 210000, China
| | - Jianjiang Wang
- Department of General Surgery, Jingjiang People's Hospital, Jingjiang, Jiangsu, 214500, China
| | - Wenzhong Zhang
- Department of Otolaryngology, East Theater General Hospital of PLA, Nanjing, Jiangsu, 210000, China
| | - Ji Yong
- Department of Otolaryngology, East Theater General Hospital of PLA, Nanjing, Jiangsu, 210000, China.
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Novel aptasensor-based assay of sonic hedgehog ligand for detection of portal vein invasion of hepatocellular carcinoma. Biosens Bioelectron 2020; 174:112738. [PMID: 33257185 DOI: 10.1016/j.bios.2020.112738] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/15/2020] [Accepted: 10/16/2020] [Indexed: 12/13/2022]
Abstract
The high expression of sonic hedgehog ligand (SHh) is closely correlated to the metastasis, drug resistance and poor prognosis of hepatocellular carcinoma (HCC). Therefore, sensitive, specific and efficient detection methods for SHh are needed for the early diagnosis and assessment of prognosis. Herein, an aptamer, AP32 that specifically binds to SHh (KD = 25.7 ± 4.1 nM) was obtained by SELEX technology with further optimization. In vivo experiments confirmed that AP32 has the potential to be an imaging probe for Huh-7 cell-derived xenograft. The interaction mode in 3-dimensional configuration between the aptamer and SHh was established by molecular simulation and confirmed by mutations at key sites of the aptamer. An aptasensor-based assay was successfully developed by conjugating Texas-Red-labeled AP32 to microbeads, and was used to analyze SHh content in hepatoma cell lysates, serum and HCC specimens. The method exhibited a broad detection range from 0.07 to 62.5 nM with a low detection limit of 69 pM, and a recovery rate of 104.6 ± 3.9% in serum. When the assay was used to measure SHh content in tissue lysates, the results demonstrated that it possessed 57.1% positivity, 100% specificity in distinguishing 28 HCC specimens from normal tissues, and was compensatory for detection of HCC in AFP-negative cases. Moreover, elevated SHh levels are indicative of portal vein invasion at 77.8% positive rate. This novel aptasensor-based SHh assay may offer a reliable means in predicting early metastasis and poor prognosis in hepatocellular carcinoma.
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Lee HY, Hong IS. Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer. Cancers (Basel) 2020; 12:cancers12102746. [PMID: 32987767 PMCID: PMC7598600 DOI: 10.3390/cancers12102746] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
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Affiliation(s)
- Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, 85 Goesan-eup, Munmu-ro, Goesan-gun, Chungcheongbuk-do 367700, Korea;
| | - In-Sun Hong
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406840, Korea
- Correspondence: ; Tel.: +82-32-899-6315; Fax: +82-32-899-6350
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Wei C, Pan Y, Zhang Y, Dai Y, Jiang L, Shi L, Yang W, Xu S, Zhang Y, Xu W, Zhang Y, Lin X, Zhang S. Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells. Cell Death Dis 2020; 11:755. [PMID: 32934215 PMCID: PMC7492405 DOI: 10.1038/s41419-020-02956-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023]
Abstract
Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2cre/+R26-SmoM2+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.
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Affiliation(s)
- Cheng Wei
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Yibin Pan
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Yinli Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Yongdong Dai
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Lingling Jiang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Libing Shi
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Weijie Yang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Shiqian Xu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Yingyi Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Wenzhi Xu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Yanling Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China
| | - Xiaona Lin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. .,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.
| | - Songying Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. .,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.
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Itraconazole inhibits the Hedgehog signaling pathway thereby inducing autophagy-mediated apoptosis of colon cancer cells. Cell Death Dis 2020; 11:539. [PMID: 32681018 PMCID: PMC7367825 DOI: 10.1038/s41419-020-02742-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/14/2022]
Abstract
Itraconazole is as an antifungal medication used to treat systemic fungal infections. Recently, it has been reported to be effective in suppressing tumor growth by inhibiting the Hedgehog signaling pathway and angiogenesis. In the present study, we investigated whether itraconazole induces autophagy-mediated cell death of colon cancer cells through the Hedgehog signaling pathway. Cell apoptosis and cell cycle distribution of the colon cancer cell lines SW-480 and HCT-116 were detected by flow cytometry and terminal TUNEL assay. Autophagy and signal proteins were detected by western blotting and cell proliferation-associated antigen Ki-67 was measured using immunohistochemistry. The images of autophagy flux and formation of autophagosomes were observed by laser scanning confocal and/or transmission electron microscopy. Colon cancer cell xenograft mouse models were also established. Itraconazole treatment inhibited cell proliferation via G1 cell cycle arrest as well as autophagy-mediated apoptosis of SW-480 and HCT-116 colon cancer cells. In addition, the Hedgehog pathway was found to be involved in activation of itraconazole-mediated autophagy. After using the Hedgehog agonist recombinant human Sonic Hedgehog (rhshh), itraconazole could counteract the activation of rhshh. Moreover, treatment with itraconazole produced significant cancer inhibition in HCT-116-bearing mice. Thus, itraconazole may be a potential and effective therapy for the treatment of colon cancer.
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Wang Y, Zhu F, Zhang Y, Chen C, Lai Y, Sun J, Chen S, Qiu P, Gao J, Deng G. Shikonin suppresses trophoblast cell growth via regulation of GLI1, and p62 mediated caspase 8 activation. Reprod Toxicol 2020; 95:104-112. [PMID: 32461113 DOI: 10.1016/j.reprotox.2020.05.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 05/10/2020] [Accepted: 05/18/2020] [Indexed: 10/24/2022]
Abstract
Unruptured ectopic pregnancy (UEP) is a common cause of morbidity and, occasionally, of mortality in women of reproductive age. Pharmacological intervention is a common therapeutic approach for early-stage UEP. Herein, we investigated the cytotoxic effect and novel mechanism of shikonin, a natural naphthoquinone pigment purified from Lithospermum erythrorhizon, in human trophoblast cells. These data demonstrated that shikonin suppressed proliferation and induced apoptosis in a time-dependent manner in HTR-8/SVneo cells. Shikonin blocked autophagic flux and promoted p62 interaction with caspase 8, resulting in caspase 8 activation. Moreover, shikonin suppressed GLI1 expression, and GLI1 overexpression attenuated shikonin-induced cell apoptosis. Although silencing GLI1 slightly promoted cell apoptosis, p62 overexpression enhanced GLI1 silencing-induced cell apoptosis by activating caspase 8. Furthermore, rapamycin increased shikonin-induced cell apoptosis in HTR-8/SVneo cells, whereas 3-MA attenuated the cytotoxic effect of shikonin. In conclusion, shikonin suppressed trophoblast cell growth by silencing GLI1 and increasing p62 co-mediated activation of caspase 8, which suggested a potential novel therapeutic target for UEP.
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Affiliation(s)
- Yanxi Wang
- First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Fangfang Zhu
- First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Yingxuan Zhang
- First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Chunlin Chen
- First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Yuling Lai
- First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Jianhua Sun
- First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Si Chen
- First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Pin Qiu
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Jie Gao
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Gaopi Deng
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
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Liu YC, Yeh CT, Lin KH. Cancer Stem Cell Functions in Hepatocellular Carcinoma and Comprehensive Therapeutic Strategies. Cells 2020; 9:cells9061331. [PMID: 32466488 PMCID: PMC7349579 DOI: 10.3390/cells9061331] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/22/2020] [Accepted: 05/22/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant cause of cancer-related mortality owing to resistance to traditional treatments and tumor recurrence after therapy, which leads to poor therapeutic outcomes. Cancer stem cells (CSC) are a small subset of tumor cells with the capability to influence self-renewal, differentiation, and tumorigenesis. A number of surface markers for liver cancer stem cell (LCSC) subpopulations (EpCAM, CD133, CD44, CD13, CD90, OV-6, CD47, and side populations) in HCC have been identified. LCSCs play critical roles in regulating HCC stemness, self-renewal, tumorigenicity, metastasis, recurrence, and therapeutic resistance via genetic mutations, epigenetic disruption, signaling pathway dysregulation, or alterations microenvironment. Accumulating studies have shown that biomarkers for LCSCs contribute to diagnosis and prognosis prediction of HCC, supporting their utility in clinical management and development of therapeutic strategies. Preclinical and clinical analyses of therapeutic approaches for HCC using small molecule inhibitors, oncolytic measles viruses, and anti-surface marker antibodies have demonstrated selective, efficient, and safe targeting of LCSC populations. The current review focuses on recent reports on the influence of LCSCs on HCC stemness, tumorigenesis, and multiple drug resistance (MDR), along with LCSC-targeted therapeutic strategies for HCC.
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Affiliation(s)
- Yu-Chin Liu
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan;
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan;
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Correspondence: ; Tel./Fax: +886-3-211-8263
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50
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Wu WL, Papagiannakopoulos T. The Pleiotropic Role of the KEAP1/NRF2 Pathway in Cancer. ANNUAL REVIEW OF CANCER BIOLOGY 2020. [DOI: 10.1146/annurev-cancerbio-030518-055627] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The unregulated proliferative capacity of many tumors is dependent on dysfunctional nutrient utilization and ROS (reactive oxygen species) signaling to sustain a deranged metabolic state. Although it is clear that cancers broadly rely on these survival and signaling pathways, how they achieve these aims varies dramatically. Mutations in the KEAP1/NRF2 pathway represent a potent cancer adaptation to exploit native cytoprotective pathways that involve both nutrient metabolism and ROS regulation. Despite activating these advantageous processes, mutations within KEAP1/ NRF2 are not universally selected for across cancers and instead appear to interact with particular tumor driver mutations and tissues of origin. Here, we highlight the relationship between the KEAP1/NRF2 signaling axis and tumor biology with a focus on genetic mutation, metabolism, immune regulation, and treatment implications and opportunities. Understanding the dysregulation of KEAP1 and NRF2 provides not only insight into a commonly mutated tumor suppressor pathway but also a window into the factors dictating the development and evolution of many cancers.
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Affiliation(s)
- Warren L. Wu
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
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