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Khoonkari M, Liang D, Kamperman M, van Rijn P, Kruyt FAE. The unfolded protein response sensor PERK mediates mechanical stress-induced maturation of focal adhesion complexes in glioblastoma cells. FEBS Lett 2024; 598:3021-3035. [PMID: 39152526 PMCID: PMC11665954 DOI: 10.1002/1873-3468.14996] [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: 05/01/2024] [Revised: 06/21/2024] [Accepted: 07/08/2024] [Indexed: 08/19/2024]
Abstract
Stiffening of the brain extracellular matrix (ECM) in glioblastoma promotes tumor progression. Previously, we discovered that protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) plays a role in glioblastoma stem cell (GSC) adaptation to matrix stiffness through PERK/FLNA-dependent F-actin remodeling. Here, we examined the involvement of PERK in detecting stiffness changes via focal adhesion complex (FAC) formation. Compared to control GSCs, PERK-deficient GSCs show decreased vinculin and tensin expression, while talin and integrin-β1 remain constant. Furthermore, vimentin was also reduced while tubulin increased, and a stiffness-dependent increase of the differentiation marker GFAP expression was absent in PERK-deficient GSCs. In conclusion, our study reveals a novel role for PERK in FAC formation during matrix stiffening, which is likely linked to its regulation of F-actin remodeling.
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Affiliation(s)
- Mohammad Khoonkari
- Department of Medical OncologyUniversity of Groningen, University Medical Center GroningenThe Netherlands
- Zernike Institute for Advanced MaterialsUniversity of GroningenThe Netherlands
| | - Dong Liang
- Department of Medical OncologyUniversity of Groningen, University Medical Center GroningenThe Netherlands
| | - Marleen Kamperman
- Zernike Institute for Advanced MaterialsUniversity of GroningenThe Netherlands
| | - Patrick van Rijn
- Department of Biomedical Engineering‐FB40University of Groningen, University Medical Center GroningenThe Netherlands
- W.J. Kolff Institute for Biomedical Engineering and Materials Science‐FB41, University of Groningen, University Medical Center GroningenThe Netherlands
| | - Frank A. E. Kruyt
- Department of Medical OncologyUniversity of Groningen, University Medical Center GroningenThe Netherlands
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2
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Taylor MA, Kandyba E, Halliwill K, Delrosario R, Khoroshkin M, Goodarzi H, Quigley D, Li YR, Wu D, Bollam SR, Mirzoeva OK, Akhurst RJ, Balmain A. Stem-cell states converge in multistage cutaneous squamous cell carcinoma development. Science 2024; 384:eadi7453. [PMID: 38815020 DOI: 10.1126/science.adi7453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 04/05/2024] [Indexed: 06/01/2024]
Abstract
Stem cells play a critical role in cancer development by contributing to cell heterogeneity, lineage plasticity, and drug resistance. We created gene expression networks from hundreds of mouse tissue samples (both normal and tumor) and integrated these with lineage tracing and single-cell RNA-seq, to identify convergence of cell states in premalignant tumor cells expressing markers of lineage plasticity and drug resistance. Two of these cell states representing multilineage plasticity or proliferation were inversely correlated, suggesting a mutually exclusive relationship. Treatment of carcinomas in vivo with chemotherapy repressed the proliferative state and activated multilineage plasticity whereas inhibition of differentiation repressed plasticity and potentiated responses to cell cycle inhibitors. Manipulation of this cell state transition point may provide a source of potential combinatorial targets for cancer therapy.
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Affiliation(s)
- Mark A Taylor
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Clinical Research Centre, Medical University of Bialystok, Bialystok 15-089, Poland
| | - Eve Kandyba
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Kyle Halliwill
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- AbbVie, South San Francisco, CA 94080, USA
| | - Reyno Delrosario
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Matvei Khoroshkin
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Hani Goodarzi
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94518, USA
- Department of Urology, University of California San Francisco, San Francisco, CA 94518, USA
- Arc Institute, Palo Alto, CA 94304, USA
| | - David Quigley
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Urology, University of California San Francisco, San Francisco, CA 94518, USA
- Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA 94518, USA
| | - Yun Rose Li
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
- Department of Cancer Genetics & Epigenetics, City of Hope National Medical Center, Duarte, CA 91010, USA
- Division of Quantitative Medicine & Systems Biology, Translational Genomics Research Institute, Phoenix, CA 85004, USA
| | - Di Wu
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Saumya R Bollam
- Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94518, USA
| | - Olga K Mirzoeva
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Rosemary J Akhurst
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94518, USA
| | - Allan Balmain
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94518, USA
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Khan SU, Fatima K, Aisha S, Malik F. Unveiling the mechanisms and challenges of cancer drug resistance. Cell Commun Signal 2024; 22:109. [PMID: 38347575 PMCID: PMC10860306 DOI: 10.1186/s12964-023-01302-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 08/30/2023] [Indexed: 02/15/2024] Open
Abstract
Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance. Video Abstract.
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Affiliation(s)
- Sameer Ullah Khan
- Division of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Holcombe Blvd, Houston, TX, 77030, USA.
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar-190005, Jammu and Kashmir, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
| | - Kaneez Fatima
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar-190005, Jammu and Kashmir, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Shariqa Aisha
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar-190005, Jammu and Kashmir, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Fayaz Malik
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar-190005, Jammu and Kashmir, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
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Wang SSY. Advancing biomarker development for diagnostics and therapeutics using solid tumour cancer stem cell models. TUMORI JOURNAL 2024; 110:10-24. [PMID: 36964664 DOI: 10.1177/03008916231158411] [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: 03/26/2023]
Abstract
The cancer stem cell model hopes to explain solid tumour carcinogenesis, tumour progression and treatment failure in cancers. However, the cancer stem cell model has led to minimal clinical translation to cancer stem cell biomarkers and targeted therapies in solid tumours. Many reasons underlie the challenges, one being the imperfect understanding of the cancer stem cell model. This review hopes to spur further research into clinically translatable cancer stem cell biomarkers through first defining cancer stem cells and their associated models. With a better understanding of these models there would be a development of more accurate biomarkers. Making the clinical translation of biomarkers into diagnostic tools and therapeutic agents more feasible.
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Ouyang L, Sun MM, Zhou PS, Ren YW, Liu XY, Wei WY, Song ZS, Lu K, Yang LX. LncRNA FOXD1-AS1 regulates pancreatic cancer stem cell properties and 5-FU resistance by regulating the miR-570-3p/SPP1 axis as a ceRNA. Cancer Cell Int 2024; 24:4. [PMID: 38167126 PMCID: PMC10763109 DOI: 10.1186/s12935-023-03181-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 12/16/2023] [Indexed: 01/05/2024] Open
Abstract
Cancer stem cells (CSCs) play a pivotal role in the pathogenesis of human cancers. Previous studies have highlighted the role of long non-coding RNA (lncRNA) in modulating the stemness of CSCs. In our investigation, we identified an upregulation of lncRNA FOXD1-AS1 in CSCs. The enforced expression of lncRNA FOXD1-AS1 promotes tumorigenesis and self-renewal in pancreatic cancer CSCs. Conversely, the knockdown of lncRNA FOXD1-AS1 inhibits tumorigenesis and self-renewal in pancreatic cancer CSCs. Furthermore, our findings reveal that lncRNA FOXD1-AS1 enhances self-renewal and tumorigenesis in pancreatic cancer CSCs by up-regulating osteopontin/secreted phosphoprotein 1(SPP1) and acting as a ceRNA to sponge miR-570-3p in pancreatic cancer (PC) CSCs. Additionally, lncRNA FOXD1-AS1 depleted pancreatic cancer cells exhibit heightened sensitivity to 5-FU-indued cell growth inhibition and apoptosis. Analysis of patient-derived xenografts (PDX) indicates that a low level of lncRNA FOXD1-AS1 may serve as a predictor of 5-FU benefits in PC patients. Moreover, the introduction of SPP1 can reverse the sensitivity of lncRNA FOXD1-AS1-knockdown PC cells to 5-FU-induced cell apoptosis. Importantly, molecular studies have indicated that the elevated levels of lncRNAFOXD1-AS1 in PC are facilitated through METTL3 and YTHDF1-dependent m6A methylation. In summary, our results underscore the critical functions of lncRNA FOXD1-AS1 in the self-renewal and tumorigenesis of pancreatic cancer CSCs, positioning lncRNA FOXD1-AS1 as a promising therapeutic target for PC.
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Affiliation(s)
- Liu Ouyang
- Department of Hepatobiliary and Pancreatic (HBP) Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
- Department of Hepatobiliary and Pancreatic (HBP) Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Min-Min Sun
- Department of Hepatic Surgery I, The Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
| | - Ping-Sheng Zhou
- Department of Ultrasonic Intervention, The Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
| | - Yi-Wei Ren
- Department of Hepatobiliary and Pancreatic (HBP) Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
- Department of Hepatobiliary and Pancreatic (HBP) Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Xin-Yu Liu
- Department of Hepatobiliary and Pancreatic (HBP) Surgery, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Wan-Ying Wei
- Department of Biliary Tract Surgery II, The Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
| | - Zhen-Shun Song
- Department of Hepatobiliary and Pancreatic (HBP) Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
| | - Kai Lu
- Department of Biliary Tract Surgery II, The Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
| | - Li-Xue Yang
- Department of Biliary Tract Surgery II, The Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
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Lu XJ, Gao WW, Li JC, Qin SF. miRNA-381 regulates renal cancer stem cell properties and sunitinib resistance via targeting SOX4. Biochem Biophys Rep 2023; 36:101566. [PMID: 37965067 PMCID: PMC10641571 DOI: 10.1016/j.bbrep.2023.101566] [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: 08/02/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 11/16/2023] Open
Abstract
Cancer stem cells (CSCs) are crucial in the pathogenesis of human cancers. Existing studies reported that microRNA (miRNA) modulates the stemness of CSCs. We discovered that renal cell CSCs have suppressed miR-381. Suppression of miR-381 promotes renal cell tumorigenesis and CSC-like properties. Furthermore, the forced expression of miR-381 prevents the renal cell tumorigenesis and CSC-like properties. Mechanistically, renal cell CSCs have been found to interact with SOX4 through miR-381 directly. miR-381 inhibits renal cell CSC-like properties and tumorigenesis via downregulating SOX4. Examination of the patient-derived xenografts (PDX) and patient cohorts reveals that miR-381 may be able to forecast the advantages of Sunitinib in RCC patients. Moreover, the introduction of SOX4 could reverse the sensitivity of miR-381 overexpression RCC cells to Sunitinib-induced cell apoptosis. These results indicated that miR-381 is critical in renal cell CSC-like properties and tumorigenesis, making it the ideal therapeutic target for RCC.
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Affiliation(s)
- Xiao-jun Lu
- Department of Urology, Shanghai FourthPeople's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Wen-wen Gao
- Department of Oncology, Shidong Hospital, Affiliated to University of Shanghai for Science and Technology, Shanghai, China
| | - Jia-cheng Li
- Department of Urology, Shanghai FourthPeople's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Sheng-Fei Qin
- Department of Urology, Shanghai FourthPeople's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
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Kim S, Park JM, Park S, Jung E, Ko D, Park M, Seo J, Nam KD, Kang YK, Lee K, Farrand L, Kim YJ, Kim JY, Seo JH. Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR. J Exp Clin Cancer Res 2023; 42:292. [PMID: 37924112 PMCID: PMC10625208 DOI: 10.1186/s13046-023-02866-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/16/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC. METHODS The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA. RESULTS DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function. CONCLUSIONS Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.
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Affiliation(s)
- Seongjae Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
| | - Jung Min Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
| | - Soeun Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
| | - Eunsun Jung
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
| | - Dongmi Ko
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
| | - Minsu Park
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
| | - Juyeon Seo
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
| | - Kee Dal Nam
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
| | - Yong Koo Kang
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
| | - Kyoungmin Lee
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea
| | - Lee Farrand
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Yoon-Jae Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea.
| | - Ji Young Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea.
| | - Jae Hong Seo
- Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
- Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
- Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea.
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Seyama Y, Sudo K, Hirose S, Hamano Y, Yamada T, Hiroyama T, Sasaki R, Hirai MY, Hyodo I, Tsuchiya K, Nakamura Y. Identification of a gene set that maintains tumorigenicity of the hepatocellular carcinoma cell line Li-7. Hum Cell 2023; 36:2074-2086. [PMID: 37610679 PMCID: PMC10587214 DOI: 10.1007/s13577-023-00967-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 07/31/2023] [Indexed: 08/24/2023]
Abstract
The identification and development of therapeutic targets in cancer stem cells that lead to tumor development, recurrence, metastasis, and drug resistance is an important goal in cancer research. The hepatocellular carcinoma cell line Li-7 contains functionally different types of cells. Cells with tumor-forming activity are enriched in cancer stem cell-like CD13+CD166- cells and this cell population gradually decreases during culture in conventional culture medium (RPMI1640 containing 10% fetal bovine serum). When Li-7 cells are cultured in mTeSR1, a medium developed for human pluripotent stem cells, CD13+CD166- cells, and their tumorigenicity is maintained. Here, we sought to identify the mechanisms of tumorigenicity in this sub-population. We compared gene expression profiles of CD13+CD166- cells with other cell sub-populations and identified nine overexpressed genes (ENPP2, SCGN, FGFR4, MCOLN3, KCNJ16, SMIM22, SMIM24, SERPINH1, and TMPRSS2) in CD13+CD166- cells. After transfer from mTeSR1 to RPMI1640 containing 10% fetal bovine serum, the expression of these nine genes decreased in Li-7 cells and they lost tumorigenicity. In contrast, when these genes of Li-7 cells were forcibly expressed in cultures using RPMI1640 containing 10% fetal bovine serum, Li-7 cells maintained tumorigenicity. A metabolome analysis using capillary electrophoresis-mass spectrometry showed that two metabolic pathways, "Alanine, aspartate and glutamate metabolism" and "Arginine biosynthesis" were activated in cancer stem-cell-like cells. Our analyses here showed potential therapeutic target genes and metabolites for treatment of cancer stem cells in hepatocellular carcinoma.
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Affiliation(s)
- Yusuke Seyama
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
- Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
| | - Kazuhiro Sudo
- Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan.
| | - Suguru Hirose
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
- Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
| | - Yukako Hamano
- Department of Gastroenterology, Hitachi General Hospital, Hitachi, Japan
| | - Takeshi Yamada
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
- Division of Clinical Research and Regional Innovation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takashi Hiroyama
- Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
| | - Ryosuke Sasaki
- RIKEN Center for Sustainable Resource Science, Yokohama, Japan
| | | | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Kiichiro Tsuchiya
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yukio Nakamura
- Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan.
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9
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Safi S, Ahmadzade M, Karimi S, Akbari ME, Rouientan H, Abolhosseini M, Rezaei Kanavi M, Khorrami Z. A registration trend in eyelid skin cancers and associated risk factors in Iran, 2005-2016. BMC Cancer 2023; 23:924. [PMID: 37777736 PMCID: PMC10543867 DOI: 10.1186/s12885-023-11414-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 09/17/2023] [Indexed: 10/02/2023] Open
Abstract
BACKGROUND Eyelid skin cancers are the most prevalent ophthalmic malignancies. This study aimed to evaluate the association of the Human Development Index (HDI) and lifestyle risk factors with eyelid skin cancers in Iran. METHODS This ecological study analyzed the data collected from the Iranian National Population-based Cancer Registry (2005-2016). The data on provincial-level eyelid skin cancer risk factors were obtained from national sources. The association between provincial HDI and lifestyle risk factors with the prevalence of eyelid skin cancers was assessed. RESULTS The mean 12-year age-standardized incidence rate (ASIR) of eyelid skin cancers was 16.22 per 100,000 (9,104 cases). The overall ASIR showed an upward trend with an estimated annual average increase of 0.006 per year. There were positive correlations between the prevalence of overall eyelid skin cancers and provincial HDI, smoking, and obesity (r = 0.32, 0.42, and 0.37, respectively). In multivariate analysis, obesity/overweight remained a positive predictor for high prevalence of total eyelid skin cancers (OR = 1.97, 95%CI = 1.08-3.58, P = 0.026), carcinoma (2.10, 1.15-3.83, P = 0.015), and basal cell carcinoma (1.48, 0.99-2.20, P = 0.054). CONCLUSIONS An increasing trend in ASIR of eyelid skin cancers was observed in more than a decade in Iran which was positively associated with provincial HDI and prevalence of obesity. The findings of the study highlight the importance of promotional programs for preventing obesity/overweight and appropriate allocation of screening facilities based on the HDI level.
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Affiliation(s)
- Sare Safi
- Ophthalmic Epidemiology Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Optometry, School of Rehabilitation, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohadese Ahmadzade
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Karimi
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Hamidreza Rouientan
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Abolhosseini
- Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhgan Rezaei Kanavi
- Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Zahra Khorrami
- Ophthalmic Epidemiology Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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10
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Khan SU, Rayees S, Sharma P, Malik F. Targeting redox regulation and autophagy systems in cancer stem cells. Clin Exp Med 2023; 23:1405-1423. [PMID: 36473988 DOI: 10.1007/s10238-022-00955-5] [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: 10/24/2022] [Accepted: 11/16/2022] [Indexed: 12/12/2022]
Abstract
Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).
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Affiliation(s)
- Sameer Ullah Khan
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sheikh Rayees
- PK PD Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India
| | - Pankaj Sharma
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India
| | - Fayaz Malik
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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11
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Saini KK, Chaturvedi P, Sinha A, Singh MP, Khan MA, Verma A, Nengroo MA, Satrusal SR, Meena S, Singh A, Srivastava S, Sarkar J, Datta D. Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer. Redox Biol 2023; 65:102833. [PMID: 37536085 PMCID: PMC10412847 DOI: 10.1016/j.redox.2023.102833] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/05/2023] Open
Abstract
Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.
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Affiliation(s)
- Krishan Kumar Saini
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India
| | - Priyank Chaturvedi
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Abhipsa Sinha
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Manish Pratap Singh
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Muqtada Ali Khan
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Ayushi Verma
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Mushtaq Ahmad Nengroo
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Saumya Ranjan Satrusal
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India
| | - Sanjeev Meena
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Akhilesh Singh
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Sameer Srivastava
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, 211004, India
| | - Jayanta Sarkar
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India
| | - Dipak Datta
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.
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12
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Taylor MA, Kandyba E, Halliwill K, Delrosario R, Koroshkin M, Goodarzi H, Quigley D, Li YR, Wu D, Bollam S, Mirzoeva O, Akhurst RJ, Balmain A. Gene networks reveal stem-cell state convergence during preneoplasia and progression to malignancy in multistage skin carcinogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.08.539863. [PMID: 37215032 PMCID: PMC10197547 DOI: 10.1101/2023.05.08.539863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Adult mammalian stem cells play critical roles in normal tissue homeostasis, as well as in tumor development, by contributing to cell heterogeneity, plasticity, and development of drug resistance. The relationship between different types of normal and cancer stem cells is highly controversial and poorly understood. Here, we carried out gene expression network analysis of normal and tumor samples from genetically heterogeneous mice to create network metagenes for visualization of stem-cell networks, rather than individual stem-cell markers, at the single-cell level during multistage carcinogenesis. We combined this approach with lineage tracing and single-cell RNASeq of stem cells and their progeny, identifying a previously unrecognized hierarchy in which Lgr6+ stem cells from tumors generate progeny that express a range of other stem-cell markers including Sox2, Pitx1, Foxa1, Klf5, and Cd44. Our data identify a convergence of multiple stem-cell and tumor-suppressor pathways in benign tumor cells expressing markers of lineage plasticity and oxidative stress. This same single-cell population expresses network metagenes corresponding to markers of cancer drug resistance in human tumors of the skin, lung and prostate. Treatment of mouse squamous carcinomas in vivo with the chemotherapeutic cis-platin resulted in elevated expression of the genes that mark this cell population. Our data have allowed us to create a simplified model of multistage carcinogenesis that identifies distinct stem-cell states at different stages of tumor progression, thereby identifying networks involved in lineage plasticity, drug resistance, and immune surveillance, providing a rich source of potential targets for cancer therapy.
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Affiliation(s)
- Mark A. Taylor
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Eve Kandyba
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Kyle Halliwill
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Reyno Delrosario
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Matvei Koroshkin
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Hani Goodarzi
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - David Quigley
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Yun Rose Li
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Di Wu
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Saumya Bollam
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Olga Mirzoeva
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Rosemary J. Akhurst
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
| | - Allan Balmain
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; San Francisco, 94158, USA
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13
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Luo Q, Liu P, Yu P, Qin T. Cancer Stem Cells are Actually Stem Cells with Disordered Differentiation: the Monophyletic Origin of Cancer. Stem Cell Rev Rep 2023; 19:827-838. [PMID: 36648606 PMCID: PMC10185654 DOI: 10.1007/s12015-023-10508-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2023] [Indexed: 01/18/2023]
Abstract
Cancer stem cells (CSCs) play an important role in cancer development. Based on advancements in CSC research, we propose a monophyletic model of cancer. This model is based on the idea that CSCs are stem cells with disordered differentiation whose original purpose was to repair damaged tissues. Inflammatory responses and damage repair signals are crucial for the creation and maintenance of CSCs. Normal quiescent stem cells are activated by environmental stimulation, such as an inflammatory response, and undergo cell division and differentiation. In the initial stage of cancer development, stem cell differentiation leads to heteromorphism due to the accumulation of gene mutations, resulting in the development of metaplasia or precancerosis. In the second stage, accumulated mutations induce poor differentiation and lead to cancer development. The monophyletic model illustrates the evolution, biological behavior, and hallmarks of CSCs, proposes a concise understanding of the origin of cancer, and may encourage a novel therapeutic approach.
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Affiliation(s)
- Qiankun Luo
- Department of Hepatobilliary and Pancreatic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Jinshui District, No. 7, Weiwu Rd., Zhengzhou, 450003, Henan, China
| | - Pan Liu
- Department of Hepatobilliary and Pancreatic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Jinshui District, No. 7, Weiwu Rd., Zhengzhou, 450003, Henan, China
| | - Pengfei Yu
- Department of Hepatobilliary and Pancreatic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Jinshui District, No. 7, Weiwu Rd., Zhengzhou, 450003, Henan, China
| | - Tao Qin
- Department of Hepatobilliary and Pancreatic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Jinshui District, No. 7, Weiwu Rd., Zhengzhou, 450003, Henan, China.
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14
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Han S, Chen X, Li Z. Innate Immune Program in Formation of Tumor-Initiating Cells from Cells-of-Origin of Breast, Prostate, and Ovarian Cancers. Cancers (Basel) 2023; 15:757. [PMID: 36765715 PMCID: PMC9913549 DOI: 10.3390/cancers15030757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/18/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023] Open
Abstract
Tumor-initiating cells (TICs), also known as cancer stem cells (CSCs), are cancer cells that can initiate a tumor, possess self-renewal capacity, and can contribute to tumor heterogeneity. TICs/CSCs are developed from their cells-of-origin. In breast, prostate, and ovarian cancers, progenitor cells for mammary alveolar cells, prostate luminal (secretory) cells, and fallopian tube secretory cells are the preferred cellular origins for their corresponding cancer types. These luminal progenitors (LPs) express common innate immune program (e.g., Toll-like receptor (TLR) signaling)-related genes. Microbes such as bacteria are now found in breast, prostate, and fallopian tube tissues and their corresponding cancer types, raising the possibility that their LPs may sense the presence of microbes and trigger their innate immune/TLR pathways, leading to an inflammatory microenvironment. Crosstalk between immune cells (e.g., macrophages) and affected epithelial cells (e.g., LPs) may eventually contribute to formation of TICs/CSCs from their corresponding LPs, in part via STAT3 and/or NFκB pathways. As such, TICs/CSCs can inherit expression of innate-immunity/TLR-pathway-related genes from their cells-of-origin; the innate immune program may also represent their unique vulnerability, which can be explored therapeutically (e.g., by enhancing immunotherapy via augmenting TLR signaling).
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Affiliation(s)
- Sen Han
- Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Xueqing Chen
- Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Zhe Li
- Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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15
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Ghatak S, Hascall VC, Karamanos N, Markwald RR, Misra S. Chemotherapy induces feedback up-regulation of CD44v6 in colorectal cancer initiating cells through β-catenin/MDR1 signaling to sustain chemoresistance. Front Oncol 2022; 12:906260. [PMID: 36330477 PMCID: PMC9623568 DOI: 10.3389/fonc.2022.906260] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/15/2022] [Indexed: 08/05/2023] Open
Abstract
Chemoresistance in colorectal cancer initiating cells (CICs) involves the sustained activation of multiple drug resistance (MDR) and WNT/β-catenin signaling pathways, as well as of alternatively spliced-isoforms of CD44 containing variable exon-6 (CD44v6). In spite of its importance, mechanisms underlying the sustained activity of WNT/β-catenin signaling have remained elusive. The presence of binding elements of the β-catenin-interacting transcription factor TCF4 in the MDR1 and CD44 promoters suggests that crosstalk between WNT/β-catenin/TCF4-activation and the expression of the CD44v6 isoform mediated by FOLFOX, a first-line chemotherapeutic agent for colorectal cancer, could be a fundamental mechanism of FOLFOX resistance. Our results identify that FOLFOX treatment induced WNT3A secretion, which stimulated a positive feedback loop coupling β-catenin signaling and CD44v6 splicing. In conjunction with FOLFOX induced WNT3A signal, specific CD44v6 variants produced by alternative splicing subsequently enhance the late wave of WNT/β-catenin activation to facilitate cell cycle progression. Moreover, we revealed that FOLFOX-mediated sustained WNT signal requires the formation of a CD44v6-LRP6-signalosome in caveolin microdomains, which leads to increased FOLFOX efflux. FOLFOX-resistance in colorectal CICs occurs in the absence of tumor-suppressor disabled-2 (DAB2), an inhibitor of WNT/β-catenin signaling. Conversely, in sensitive cells, DAB2 inhibition of WNT-signaling requires interaction with a clathrin containing CD44v6-LRP6-signalosome. Furthermore, full-length CD44v6, once internalized through the caveolin-signalosome, is translocated to the nucleus where in complex with TCF4, it binds to β-catenin/TCF4-regulated MDR1, or to CD44 promoters, which leads to FOLFOX-resistance and CD44v6 transcription through transcriptional-reprogramming. These findings provide evidence that targeting CD44v6-mediated LRP6/β-catenin-signaling and drug efflux may represent a novel approach to overcome FOLFOX resistance and inhibit tumor progression in colorectal CICs. Thus, sustained drug resistance in colorectal CICs is mediated by overexpression of CD44v6, which is both a functional biomarker and a therapeutic target in colorectal cancer.
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Affiliation(s)
- Shibnath Ghatak
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department Natural Sciences, Trident Technical College, North Charleston, SC, United States
| | - Vincent C. Hascall
- Department of Biomedical Engineering/ND20, Cleveland Clinic, Cleveland, OH, United States
| | - Nikos Karamanos
- University of Patras, Matrix Pathobiology Res. Group, Department of Chemistry, Patras, Greece
| | - Roger R. Markwald
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Suniti Misra
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department Natural Sciences, Trident Technical College, North Charleston, SC, United States
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16
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Li Y, Hu J, Guo D, Ma W, Zhang X, Zhang Z, Lu G, He S. LncRNA SNHG5 promotes the proliferation and cancer stem cell-like properties of HCC by regulating UPF1 and Wnt-signaling pathway. Cancer Gene Ther 2022; 29:1373-1383. [PMID: 35338348 PMCID: PMC9576592 DOI: 10.1038/s41417-022-00456-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 02/10/2022] [Accepted: 03/04/2022] [Indexed: 12/22/2022]
Abstract
The role of long noncoding RNA (lncRNAs) had been demonstrated in different types of cancer, including hepatocellular carcinoma. This study was intended to investigate the role of lncRNA small nucleolar RNA host gene 5 (SNHG5) in HCC proliferation and the liver CSC-like properties. Through functional experiments, we determined that knockdown of SNHG5 repressed HCC cell proliferation and CSC-like properties, while over-expression of SNHG5 promoted cell growth. At the same time, CSC markers (CD44, CD133, and ALDH1) and related transcription factors (OCT4, SOX2, and NANOG) were downregulated when SNHG5 was knocked down. Mechanically, RNA immunoprecipitation (RIP) and RNA pulldown assay showed that SNHG5 regulated the proliferation and CSC-like properties of HCC by binding UPF1. Further investigations showed that expression of critical components of Wnt/β-catenin pathway (β-catenin, TCF4, c-myc, cyclinD1, and c-Jun) were upregulated with depletion of UPF1 in liver CSCs, which were downregulated with depletion of SNHG5. After use of the inhibitor of Wnt/β-catenin pathway, the formation of liver CSCs sphere decreased. Taken together, SNHG5 plays a critical role to promote HCC cell proliferation and cancer stem cell-like properties via UPF1 and Wnt/β-catenin pathway.
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Affiliation(s)
- Yarui Li
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Junbi Hu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Dan Guo
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Wenhui Ma
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Xu Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Zhiyong Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Guifang Lu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China
| | - Shuixiang He
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
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17
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Nengroo MA, Khan MA, Verma A, Datta D. Demystifying the CXCR4 conundrum in cancer biology: Beyond the surface signaling paradigm. Biochim Biophys Acta Rev Cancer 2022; 1877:188790. [PMID: 36058380 DOI: 10.1016/j.bbcan.2022.188790] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 10/14/2022]
Abstract
The oncogenic chemokine duo CXCR4-CXCL12/SDF-1 (C-X-C Receptor 4-C-X-C Ligand 12/ Stromal-derived factor 1) has been the topic of intense scientific disquisitions since Muller et al., in her ground-breaking research, described this axis as a critical determinant of organ-specific metastasis in breast cancer. Elevated CXCR4 levels correlate with distant metastases, poor prognosis, and unfavourable outcomes in most solid tumors. Therapeutic impediment of the axis in clinics with Food and Drug Administration (FDA) approved inhibitors like AMD3100 or Plerixafor yield dubious results, contrary to pre-clinical developments. Clinical trials entailing inhibition of CXCR7 (C-X-C Receptor 7), another convicted chemokine receptor that exhibits affinity for CXCL12, reveal outcomes analogous to that of CXCR4-CXCL12 axis blockade. Of note, the cellular CXCR4 knockout phenotype varies largely from that of inhibitor treatments. These shaky findings pique great curiosity to delve further into the realm of this infamous chemokine receptor to provide a probable explanation. A multitude of recent reports suggests the presence of an increased intracellular CXCR4 pool in various cancers, both cytoplasmic and nuclear. This intracellular CXCR4 protein reserve seems active as it correlates with vital tumor attributes, viz. prognosis, aggressiveness, metastasis, and disease-free survival. Diminishing this entire intracellular CXCR4 load apart from the surface signals looks encouraging from a therapeutic point of view. Transcending beyond the classically accepted concept of ligand-mediated surface signaling, this review sheds new light on plausible associations of intracellularly compartmentalised CXCR4 with various aspects of tumorigenesis. Besides, this review also puts forward a comprehensive account of CXCR4 regulation in different cancers.
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Affiliation(s)
- Mushtaq Ahmad Nengroo
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India
| | - Muqtada Ali Khan
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India
| | - Ayushi Verma
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India
| | - Dipak Datta
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India.
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18
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Ghatak S, Hascall VC, Karamanos N, Markwald RR, Misra S. Interplay Between Chemotherapy-Activated Cancer Associated Fibroblasts and Cancer Initiating Cells Expressing CD44v6 Promotes Colon Cancer Resistance. Front Oncol 2022; 12:906415. [PMID: 35982950 PMCID: PMC9380598 DOI: 10.3389/fonc.2022.906415] [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: 03/28/2022] [Accepted: 06/22/2022] [Indexed: 11/14/2022] Open
Abstract
Cancer-initiating cells (CICs) drive colorectal tumor growth by their supportive niches where CICs interact with multiple cell types within the microenvironment, including cancer-associated fibroblasts (CAFs). We investigated the interplay between the CICs and the clinically relevant chemotherapeutic FOLFOX that creates the persistent tumorigenic properties of colorectal CICs, and stimulates the microenvironmental factors derived from the CAFs. We found that the CICs expressing an immunophenotype (CD44v6[+]) promote FOLFOX-resistance and that the CIC-immunophenotype was enhanced by factors secreted by CAFs after FOLFOX treatment These secreted factors included periostin, IL17A and WNT3A, which induced CD44v6 expression by activating WNT3A/β-catenin signaling. Blocking the interaction between CICs with any of these CAF-derived factors through tissue-specific conditional silencing of CD44v6 significantly reduced colorectal tumorigenic potential. To achieve this, we generated two unique vectors (floxed-pSico-CD44v6 shRNA plus Fabpl-Cre) that were encapsulated into transferrin coated PEG-PEI/(nanoparticles), which when introduced in vivo reduced tumor growth more effectively than using CD44v6-blocking antibodies. Notably, this tissue-specific conditional silencing of CD44v6 resulted in long lasting effects on self-renewal and tumor growth associated with a positive feedback loop linking WNT3A signaling and alternative-splicing of CD44. These findings have crucial clinical implications suggesting that therapeutic approaches for modulating tumor growth that currently focus on cell-autonomous mechanisms may be too limited and need to be broadened to include mechanisms that recognize the interplay between the stromal factors and the subsequent CIC-immunophenotype enrichment. Thus, more specific therapeutic approaches may be required to block a chemotherapy induced remodeling of a microenvironment that acts as a paracrine regulator to enrich CD44v6 (+) in colorectal CICs.
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Affiliation(s)
- Shibnath Ghatak
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department Natural Sciences, Trident Technical College, North Charleston, SC, United States
| | - Vincent C. Hascall
- Department of Biomedical Engineering/ND20, Cleveland Clinic, Cleveland, OH, United States
| | - Nikos Karamanos
- Department of Chemistry, University of Patras, Matrix Pathobiology Research Group, Patras, Greece
| | - Roger R. Markwald
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Suniti Misra
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department Natural Sciences, Trident Technical College, North Charleston, SC, United States
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19
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Rath S, Chakraborty D, Pradhan J, Imran Khan M, Dandapat J. Epigenomic interplay in tumor heterogeneity: Potential of epidrugs as adjunct therapy. Cytokine 2022; 157:155967. [PMID: 35905624 DOI: 10.1016/j.cyto.2022.155967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/11/2022] [Accepted: 07/13/2022] [Indexed: 11/28/2022]
Abstract
"Heterogeneity" in tumor mass has immense importance in cancer progression and therapy. The impact of tumor heterogeneity is an emerging field and not yet fully explored. Tumor heterogeneity is mainly considered as intra-tumor heterogeneity and inter-tumor heterogeneity based on their origin. Intra-tumor heterogeneity refers to the discrepancy within the same cancer mass while inter-tumor heterogeneity refers to the discrepancy between different patients having the same tumor type. Both of these heterogeneity types lead to variation in the histopathological as well as clinical properties of the cancer mass which drives disease resistance towards therapeutic approaches. Cancer stem cells (CSCs) act as pinnacle progenitors for heterogeneity development along with various other genetic and epigenetic parameters that are regulating this process. In recent times epigenetic factors are one of the most studied parameters that drive oxidative stress pathways essential during cancer progression. These epigenetic changes are modulated by various epidrugs and have an impact on tumor heterogeneity. The present review summarizes various aspects of epigenetic regulation in the tumor microenvironment, oxidative stress, and progression towards tumor heterogeneity that creates complications during cancer treatment. This review also explores the possible role of epidrugs in regulating tumor heterogeneity and personalized therapy against drug resistance.
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Affiliation(s)
- Suvasmita Rath
- Center of Environment, Climate Change and Public Health, Utkal University, Vani Vihar, Bhubaneswar 751004, Odisha, India
| | - Diptesh Chakraborty
- Department of Biotechnology, Utkal University, Bhubaneswar 751004, Odisha, India
| | - Jyotsnarani Pradhan
- Department of Biotechnology, Utkal University, Bhubaneswar 751004, Odisha, India
| | - Mohammad Imran Khan
- Department of Biochemistry, King Abdulaziz University (KAU), Jeddah 21577, Saudi Arabia; Centre of Artificial Intelligence for Precision Medicines, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Jagneshwar Dandapat
- Department of Biotechnology, Utkal University, Bhubaneswar 751004, Odisha, India; Centre of Excellence in Integrated Omics and Computational Biology, Utkal University, Bhubaneswar 751004, Odisha, India.
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20
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Mitochondrial Elongation and OPA1 Play Crucial Roles during the Stemness Acquisition Process in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14143432. [PMID: 35884493 PMCID: PMC9322438 DOI: 10.3390/cancers14143432] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/04/2022] [Accepted: 07/13/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal neoplasia and the currently used treatments are not effective in a wide range of patients. Presently, the evidence points out that cancer stem cells (CSCs) are key players during tumor development, metastasis, chemoresistance, and tumor relapse. The study of the metabolism of CSCs, specifically the mitochondrial alterations, could pave the way to the discovery of new therapeutical targets. In this study, we show that during progressive de-differentiation, pancreatic CSCs undergo changes in mitochondrial mass, dynamics, and function. Interestingly, the silencing of OPA1, a protein involved in mitochondrial fusion, significantly inhibits the formation of CSCs. These results reveal new insight into mitochondria and stemness acquisition that could be useful for the design of novel potential therapies in PDAC. Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with an overall 5-year survival rate of less than 9%. The high aggressiveness of PDAC is linked to the presence of a subpopulation of cancer cells with a greater tumorigenic capacity, generically called cancer stem cells (CSCs). CSCs present a heterogeneous metabolic profile that might be supported by an adaptation of mitochondrial function; however, the role of this organelle in the development and maintenance of CSCs remains controversial. To determine the role of mitochondria in CSCs over longer periods, which may reflect more accurately their quiescent state, we studied the mitochondrial physiology in CSCs at short-, medium-, and long-term culture periods. We found that CSCs show a significant increase in mitochondrial mass, more mitochondrial fusion, and higher mRNA expression of genes involved in mitochondrial biogenesis than parental cells. These changes are accompanied by a regulation of the activities of OXPHOS complexes II and IV. Furthermore, the protein OPA1, which is involved in mitochondrial dynamics, is overexpressed in CSCs and modulates the tumorsphere formation. Our findings indicate that CSCs undergo mitochondrial remodeling during the stemness acquisition process, which could be exploited as a promising therapeutic target against pancreatic CSCs.
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Tan J, Wang Y, Sun L, Xu S, Li C, Jin X. The Origin and Evolution of Bladder Cancer Stem Cells. Front Cell Dev Biol 2022; 10:950241. [PMID: 35903544 PMCID: PMC9314767 DOI: 10.3389/fcell.2022.950241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
Bladder cancer is the most common malignant tumor of the urinary system. Bladder cancer stem cells (BCSCs) play key roles in tumor initiation, metastasis, relapse and drug-resistance. Investigation of BCSCs is of great value. On the basis of a review of normal bladder stem cells and universal cancer stem cells (CSCs), we summarize the origin of BCSCs, isolation and identification of CSCs from bladder cancer, signaling pathway of BCSCs, BCSCs targeted therapy, and relationship of BCSCs with non-muscle invasiveness and muscle invasiveness. This review aims to provide better elucidation about BCSCs, and provide constructive data for classification, prognosis, treatment and early intervention of bladder cancer.
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Affiliation(s)
- Jiufeng Tan
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital of Jilin University, Changchun, China
- Key Laboratory of Urology Tumor of Jilin Province, Changchun, China
| | - Yao Wang
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital of Jilin University, Changchun, China
- Key Laboratory of Urology Tumor of Jilin Province, Changchun, China
| | - Lihui Sun
- Zhongke Jianlan Medical Research Institute, Beijing, China
| | - Siqi Xu
- Zhongke Jianlan Medical Research Institute, Beijing, China
| | - Charles Li
- Zhongke Jianlan Medical Research Institute, Beijing, China
- *Correspondence: Charles Li, ; Xuefei Jin,
| | - Xuefei Jin
- 2nd Inpatient Area of Urology Department, China-Japan Union Hospital of Jilin University, Changchun, China
- Key Laboratory of Urology Tumor of Jilin Province, Changchun, China
- *Correspondence: Charles Li, ; Xuefei Jin,
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22
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Li Z, Zhang YY, Zhang H, Yang J, Chen Y, Lu H. Asymmetric Cell Division and Tumor Heterogeneity. Front Cell Dev Biol 2022; 10:938685. [PMID: 35859890 PMCID: PMC9289117 DOI: 10.3389/fcell.2022.938685] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 06/13/2022] [Indexed: 11/20/2022] Open
Abstract
Asymmetric cell division (ACD) gives rise to two daughter cells with different fates after mitosis and is a fundamental process for generating cell diversity and for the maintenance of the stem cell population. The cancer stem cell (CSC) theory suggests that CSCs with dysregulated self-renewal and asymmetric cell division serve as a source of intra-tumoral heterogeneity. This heterogeneity complicates the diagnosis and treatment of cancer patients, because CSCs can give rise to aggressive clones that are metastatic and insensitive to multiple drugs, or to dormant tumor cells that are difficult to detect. Here, we review the regulatory mechanisms and biological significance of asymmetric division in tumor cells, with a focus on ACD-induced tumor heterogeneity in early tumorigenesis and cancer progression. We will also discuss how dissecting the relationship between ACD and cancer may help us find new approaches for combatting this heterogeneity.
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Affiliation(s)
- Zizhu Li
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ying Yi Zhang
- Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Haomiao Zhang
- School of Stomatology, Dalian Medical University, Dalian, China
| | - Jiaxuan Yang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Yongze Chen
- College of Biological Sciences, China Agricultural University, Beijing, China
| | - Hezhe Lu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- *Correspondence: Hezhe Lu,
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Khoonkari M, Liang D, Lima MT, van der Land T, Liang Y, Sun J, Dolga A, Kamperman M, van Rijn P, Kruyt FAE. The Unfolded Protein Response Sensor PERK Mediates Stiffness-Dependent Adaptation in Glioblastoma Cells. Int J Mol Sci 2022; 23:ijms23126520. [PMID: 35742966 PMCID: PMC9223606 DOI: 10.3390/ijms23126520] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 02/05/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults. In addition to genetic causes, the tumor microenvironment (TME), including stiffening of the extracellular matrix (ECM), is a main driver of GBM progression. Mechano-transduction and the unfolded protein response (UPR) are essential for tumor-cell adaptation to harsh TME conditions. Here, we studied the effect of a variable stiff ECM on the morphology and malignant properties of GBM stem cells (GSCs) and, moreover, examined the possible involvement of the UPR sensor PERK herein. For this, stiffness-tunable human blood plasma (HBP)/alginate hydrogels were generated to mimic ECM stiffening. GSCs showed stiffness-dependent adaptation characterized by elongated morphology, increased proliferation, and motility which was accompanied by F-Actin cytoskeletal remodeling. Interestingly, in PERK-deficient GSCs, stiffness adaptation was severely impaired, which was evidenced by low F-Actin levels, the absence of F-Actin remodeling, and decreased cell proliferation and migration. This impairment could be linked with Filamin-A (FLN-A) expression, a known interactor of PERK, which was strongly reduced in PERK-deficient GSCs. In conclusion, we identified a novel PERK/FLNA/F-Actin mechano-adaptive mechanism and found a new function for PERK in the cellular adaptation to ECM stiffening.
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Affiliation(s)
- Mohammad Khoonkari
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.K.); (D.L.); (Y.L.)
- Polymer Science, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands; (J.S.); (M.K.)
| | - Dong Liang
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.K.); (D.L.); (Y.L.)
| | - Marina Trombetta Lima
- Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands; (M.T.L.); (A.D.)
| | - Tjitze van der Land
- Department of Biomedical Engineering-FB40, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands;
| | - Yuanke Liang
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.K.); (D.L.); (Y.L.)
- Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, 57 Changping Road, Shantou 515041, China
| | - Jianwu Sun
- Polymer Science, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands; (J.S.); (M.K.)
| | - Amalia Dolga
- Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV Groningen, The Netherlands; (M.T.L.); (A.D.)
| | - Marleen Kamperman
- Polymer Science, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands; (J.S.); (M.K.)
| | - Patrick van Rijn
- Department of Biomedical Engineering-FB40, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands;
- W.J. Kolff Institute for Biomedical Engineering and Materials Science-FB41, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
- Correspondence: (P.v.R.); (F.A.E.K.); Tel.: +31-50-3615531 (F.A.E.K.)
| | - Frank A. E. Kruyt
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.K.); (D.L.); (Y.L.)
- Correspondence: (P.v.R.); (F.A.E.K.); Tel.: +31-50-3615531 (F.A.E.K.)
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Terzi MY, Okuyan HM, Gülbol-Duran G, Urhan-Küçük M. Reduced Expression of PEDF and ALDH1A1 during Spheroid Transition of Lung Cancer Cells: An In Vitro Study. CYTOL GENET+ 2022. [DOI: 10.3103/s0095452722020104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Combined Targeting of AKT and mTOR Inhibits Tumor Formation of EpCAM+ and CD90+ Human Hepatocellular Carcinoma Cells in an Orthotopic Mouse Model. Cancers (Basel) 2022; 14:cancers14081882. [PMID: 35454789 PMCID: PMC9024696 DOI: 10.3390/cancers14081882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 12/12/2022] Open
Abstract
The epithelial cell adhesion molecule (EpCAM) and Thy-1 cell surface antigen (CD90) have been implicated as cancer stem cell (CSC) markers in hepatocellular carcinoma (HCC). Expression of EpCAM and CD90 on HCC cells is associated with increased tumorigenicity, metastasis and poor prognosis. In this study, we demonstrate that combined treatment with AKT and mTOR inhibitors—i.e., MK2206 and RAD001—results in a synergistic reduction in proliferation of EpCAM+ and CD90+ HCC cells cultured either as adherent cells or as tumoroids in vitro. In addition, tumor growth was reduced by combined treatment with AKT and mTOR inhibitors in an orthotopic xenograft mouse model of an EpCAM+ HCC cell line (Huh7) and primary patient-derived EpCAM+ HCC cells (HCC1) as well as a CD90+ HCC-related cell line (SK-HEP1) in vivo. However, during AKT/mTOR treatment, outgrowth of therapy-resistant tumors was observed in all mice analyzed within a few weeks. Resistance was associated in most cases with restoration of AKT signaling in the tumors, intrahepatic metastases and distant metastases. In addition, an upregulation of the p38 MAPK pathway was identified in the AKT/mTOR inhibitor-resistant tumor cells by kinome profiling. The development of resistant cells during AKT/mTOR therapy was further analyzed by red-green-blue (RGB) marking of HCC cells, which revealed an outgrowth of a large number of Huh7 cells over a period of 6 months. In summary, our data demonstrate that combined treatment with AKT and mTOR inhibitors exhibits synergistic effects on proliferation of EpCAM+ as well as CD90+ HCC cells in vitro. However, the fast development of large numbers of resistant clones under AKT/mTOR therapy observed in vitro and in the orthotopic xenotransplantation mouse model in vivo strongly suggests that this therapy alone will not be sufficient to eliminate EpCAM+ or CD90+ cancer stem cells from HCC patients.
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Aramini B, Masciale V, Grisendi G, Bertolini F, Maur M, Guaitoli G, Chrystel I, Morandi U, Stella F, Dominici M, Haider KH. Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence. Cancers (Basel) 2022; 14:cancers14040976. [PMID: 35205721 PMCID: PMC8869911 DOI: 10.3390/cancers14040976] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 02/12/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Cancer is one of the most debated problems all over the world. Cancer stem cells are considered responsible of tumor initiation, metastasis, drug resistance, and recurrence. This subpopulation of cells has been found into the tumor bulk and showed the capacity to self-renew, differentiate, up to generate a new tumor. In the last decades, several studies have been set on the molecular mechanisms behind their specific characteristics as the Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, etc. The most powerful part of CSCs is represented by the niches as “promoter” of their self-renewal and “protector” from the common oncological treatment as chemotherapy and radiotherapy. In our review article we highlighted the primary mechanisms involved in CSC tumorigenesis for the setting of further targets to control the metastatic process. Abstract Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
- Correspondence:
| | - Valentina Masciale
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Federica Bertolini
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Michela Maur
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Giorgia Guaitoli
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Isca Chrystel
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Uliano Morandi
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Franco Stella
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
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Li CC, Shen Z, Bavarian R, Yang F, Bhattacharya A. Oral Cancer: Genetics and the Role of Precision Medicine. Surg Oncol Clin N Am 2021; 29:127-144. [PMID: 31757309 DOI: 10.1016/j.soc.2019.08.010] [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] [Indexed: 12/15/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is one of the leading cancers in the world. OSCC patients are managed with surgery and/or chemoradiation. Prognoses and survival rates are dismal, however, and have not improved for more than 20 years. Recently, the concept of precision medicine was introduced, and the introduction of targeted therapeutics demonstrated promising outcomes. This article reviews the current understanding of initiation, progression, and metastasis of OSCC from both genetic and epigenetic perspectives. In addition, the applications and integration of omics technologies in biomarker discovery and drug development for treating OSCC are reviewed.
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Affiliation(s)
- Chia-Cheng Li
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
| | - Zhen Shen
- Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA
| | - Roxanne Bavarian
- Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA; Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Francis Street, Boston, MA 02115, USA
| | - Fan Yang
- Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA
| | - Aditi Bhattacharya
- Department of Oral and Maxillofacial Surgery, NYU College of Dentistry, East 24th Street, New York, NY 10010, USA
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Stem Cell Theory of Cancer: Origin of Tumor Heterogeneity and Plasticity. Cancers (Basel) 2021; 13:cancers13164006. [PMID: 34439162 PMCID: PMC8394880 DOI: 10.3390/cancers13164006] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/29/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022] Open
Abstract
In many respects, heterogeneity is one of the most striking revelations and common manifestations of a stem cell origin of cancer. We observe heterogeneity in myriad mixed tumors including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes in prostate and kidney cancers. From this perspective, we illustrate that one of the main stem-ness characteristics, i.e., the ability to differentiate into diverse and multiple lineages, is central to tumor heterogeneity. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer's stem cell versus genetic origin and nature. We propose a unified theory of cancer in which the same genetic abnormalities, epigenetic defects, and microenvironmental aberrations cause different effects and lead to different outcomes in a progenitor stem cell versus a mature progeny cell. We need to recognize that an all-encompassing genetic theory of cancer may be incomplete and obsolete. A stem cell theory of cancer provides greater universality, interconnectivity, and utility. Although genetic defects are pivotal, cellular context is paramount. When it concerns tumor heterogeneity, perhaps we need to revisit the conventional wisdom of precision medicine and revise our current practice of targeted therapy in cancer care.
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Manzo G. Specific and Aspecific Molecular Checkpoints as Potential Targets for Dismantling Tumor Hierarchy and Preventing Relapse and Metastasis Through Shielded Cytolytic Treatments. Front Cell Dev Biol 2021; 9:665321. [PMID: 34295890 PMCID: PMC8291084 DOI: 10.3389/fcell.2021.665321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/17/2021] [Indexed: 11/15/2022] Open
Abstract
I have recently theorized that several similarities exist between the tumor process and embryo development. Starting from an initial cancer stem cell (CSC0), similar to an embryonic stem cell (ESC), after implantation in a niche, primary self-renewing CSCs (CSC1s) would arise, which then generate secondary proliferating CSCs (CSC2s). From these epithelial CSCs, tertiary mesenchymal CSCs (CSC3s) would arise, which, under favorable stereotrophic conditions, by asymmetric proliferation, would generate cancer progenitor cells (CPCs) and then cancer differentiated cells (CDCs), thus giving a defined cell heterogeneity and hierarchy. CSC1s-CSC2s-CSC3s-CPCs-CDCs would constitute a defined "tumor growth module," able to generate new tumor modules, forming a spherical avascular mass, similar to a tumor sphere. Further growth in situ of this initial tumor would require implantation in the host and vascularization through the overexpression of some aspecific checkpoint molecules, such as CD44, ID, LIF, HSP70, and HLA-G. To expand and spread in the host tissues, this vascularized tumor would then carry on a real growth strategy based on other specific checkpoint factors, such as those contained in the extracellular vesicles (EVs), namely, microRNAs, messenger RNAs, long non-coding RNAs, and integrins. These EV components would be crucial in tumor progression because they can mediate intercellular communications in the surrounding microenvironment and systemically, dictating to recipient cells a new tumor-enslaved phenotype, thus determining pre-metastatic conditions. Moreover, by their induction properties, the EV contents could also frustrate in time the effects of cytolytic tumor therapies, where EVs released by killed CSCs might enter other cancer and non-cancer cells, thus giving chemoresistance, non-CSC/CSC transition (recurrence), and metastasis. Thus, antitumor cytotoxic treatments, "shielded" from the EV-specific checkpoints by suitable adjuvant agents, simultaneously targeting the aforesaid aspecific checkpoints should be necessary for dismantling the hierarchic tumor structure, avoiding recurrence and preventing metastasis.
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Quah SY, Wong CC, Wong HC, Ho KL, Abdul Manan N, Deb PK, Sagineedu SR, Stanslas J. Microarray-based identification of differentially expressed genes associated with andrographolide derivatives-induced resistance in colon and prostate cancer cell lines. Toxicol Appl Pharmacol 2021; 425:115605. [PMID: 34087331 DOI: 10.1016/j.taap.2021.115605] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/30/2021] [Accepted: 05/30/2021] [Indexed: 10/21/2022]
Abstract
Chemoresistance poses a major hurdle to cancer treatments. Andrographolide-derived SRJ09 and SRJ23 were reported to exhibit potent, selective inhibitory activities against colon and prostate cancer cells, respectively. In this study, previously developed resistant colon (HCT-116rst09) and prostate (PC-3rst23) cancer cell lines were used to elucidate the molecular mechanisms contributing to chemoresistance. Cytotoxic effects of SRJ09 and SRJ23 on both parental and resistant cells were investigated. Cell cycle distributions in HCT-116rst09 cells following SRJ09 treatment were analysed using flow cytometry. Whole-genome microarray analysis was performed on both parental and resistant cells to obtain differential gene expression profiles. Microarray data were subjected to protein-protein interaction network, functional enrichment, and pathway analyses. Reverse transcription-polymerase chain reaction (RT-PCR) was used to validate the changes in expression levels of selected genes. Besides morphological changes, HCT-116rst09 cells showed 7.0-fold resistance to SRJ09 while PC-3rst23 cells displayed a 5.5-fold resistance to SRJ23, as compared with their respective parental cells. G0/G1-phase cell cycle arrest was observed in HCT-116rst09 cells upon SRJ09 treatment. Collectively, 77 and 21 genes were found differentially modulated in HCT-116rst09 and PC-3rst23 cells, respectively. Subsequent bioinformatics analysis revealed several genes associated with FGFR4 and PI3K pathways, and cancer stemness, were chemoresistance mediators in HCT-116rst09 cells. RT-PCR confirmed the HMOX1 upregulation and ATG12 downregulation protected the PC-3rst23 cells from SRJ23 cytotoxicity. In conclusion, acquired chemoresistance to SRJ09 and SRJ23 in colon and prostate cancer cells, respectively, could be attributed to the alterations in the expression of genes such as those related to PI3K and autophagy pathways.
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Affiliation(s)
- Shun Ying Quah
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Charng Choon Wong
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Hui Chyn Wong
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Kok Lian Ho
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Nizar Abdul Manan
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Pran Kishore Deb
- Faculty of Pharmacy, P.O.BOX (1), Philadelphia University, 19392 Amman, Jordan
| | - Sreenivasa Rao Sagineedu
- Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia
| | - Johnson Stanslas
- Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
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31
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miR-93 regulates liver tumor initiating cells expansion and predicts chemotherapeutic response of patients. Arch Biochem Biophys 2021; 703:108871. [PMID: 33831356 DOI: 10.1016/j.abb.2021.108871] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 03/17/2021] [Accepted: 03/30/2021] [Indexed: 01/27/2023]
Abstract
Tumor initiating cells (T-ICs) play an important role in tumorigenesis, progression, metastasis, recurrence and drug resistance, but the underlying mechanism was not clearly elucidated. In our study, we found that miR-93 was highly expressed in liver T-ICs. Self-renewal and tumorigenesis ability of liver T-ICs were enhanced by miR-93 overexpression and attenuated by miR-93 interference. Mechanically, miR-93 regulated liver T-ICs by binding to 3'-UTR of myotubularin-related protein 3 (MTMR3). In addition, miR-93 was found highly expressed in cisplatin or sorafenib-resistant liver cancer tissues. Interference of miR-93 sensitizes hepatoma cells to cisplatin or sorafenib treatment. Clinical cohort analysis showed that Hepatocellular carcinoma (HCC) patients with low miR-93 were benefit more from TACE or sorafenib treatment. In conclusion, our study demonstrates a new regulation mechanism of liver T-ICs, a new target for HCC, and a biomarker for postoperative TACE or sorafenib.
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32
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Das PK, Islam F, Smith RA, Lam AK. Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas. Front Oncol 2021; 10:598957. [PMID: 33665161 PMCID: PMC7921694 DOI: 10.3389/fonc.2020.598957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/29/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) in esophageal cancer have a key role in tumor initiation, progression and therapy resistance. Novel therapeutic strategies to target CSCs are being tested, however, more in-depth research is necessary. Eradication of CSCs can result in successful therapeutic approaches against esophageal cancer. Recent evidence suggests that targeting signaling pathways, miRNA expression profiles and other properties of CSCs are important strategies for cancer therapy. Wnt/β-catenin, Notch, Hedgehog, Hippo and other pathways play crucial roles in proliferation, differentiation, and self-renewal of stem cells as well as of CSCs. All of these pathways have been implicated in the regulation of esophageal CSCs and are potential therapeutic targets. Interference with these pathways or their components using small molecules could have therapeutic benefits. Similarly, miRNAs are able to regulate gene expression in esophageal CSCs, so targeting self-renewal pathways with miRNA could be utilized to as a potential therapeutic option. Moreover, hypoxia plays critical roles in esophageal cancer metabolism, stem cell proliferation, maintaining aggressiveness and in regulating the metastatic potential of cancer cells, therefore, targeting hypoxia factors could also provide effective therapeutic modalities against esophageal CSCs. To conclude, additional study of CSCs in esophageal carcinoma could open promising therapeutic options in esophageal carcinomas by targeting hyper-activated signaling pathways, manipulating miRNA expression and hypoxia mechanisms in esophageal CSCs.
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Affiliation(s)
- Plabon Kumar Das
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh.,Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
| | - Robert A Smith
- Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Kelvin Grove, QLD, Australia.,Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD, Australia
| | - Alfred K Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
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33
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FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells. Int J Mol Sci 2021; 22:ijms22020753. [PMID: 33451103 PMCID: PMC7828641 DOI: 10.3390/ijms22020753] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/04/2021] [Accepted: 01/09/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1,BCL2,FZD1,GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs.
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Cheng X, Li H, Ge X, Chen L, Liu Y, Mao W, Zhao B, Yuan WE. Tumor-Microenvironment- Responsive Size-Shrinkable Drug-Delivery Nanosystems for Deepened Penetration Into Tumors. Front Mol Biosci 2020; 7:576420. [PMID: 33330618 PMCID: PMC7729065 DOI: 10.3389/fmolb.2020.576420] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/13/2020] [Indexed: 01/04/2023] Open
Abstract
Over the years, the manipulation and clinical application of drug-delivery nanosystems for cancer diseases have attracted a rapid growth of academic research interests, and some nanodrugs have been approved for clinic application. Although encouraging achievements have been made, the potency of nanomedicines in cancer treatment is far from satisfaction, and one significant reason is the inefficient penetration of nanoparticles into solid tumors. Particle size is one of the most significant features that influence diffusion ability of the drug-delivery system in tumors. Size-shrinkable drug-delivery nanosystems possess a size-switchable property that can achieve passive targeting via the enhanced permeability and retention (EPR) effect and transform into ultrasmall particles in tumors for deep penetration into tumors. The tumor microenvironment is characterized by acidic pH, hypoxia, upregulated levels of enzymes, and a redox environment. In this review, we summarize and analyze the current research progresses and challenges in tumor microenvironment responsive size-shrinkable drug-delivery nanosystems. We further expect to present some meaningful proposals and enlightenments on promoting deep penetration into tumors of nanoparticles.
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Affiliation(s)
- Xiaoliang Cheng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Houli Li
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuemei Ge
- Department of Food Science and Technology, College of Light Industry Science and Engineering, Nanjing Forestry University, Nanjing, China
| | - Lijuan Chen
- Department of Food Science and Technology, College of Light Industry Science and Engineering, Nanjing Forestry University, Nanjing, China
| | - Yao Liu
- Instrumental Analysis Center, Shanghai Jiao Tong University, Shanghai, China
| | - Wenwei Mao
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Bo Zhao
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-En Yuan
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, and School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
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35
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Sarkadi B, Homolya L, Hegedűs T. The ABCG2/BCRP transporter and its variants - from structure to pathology. FEBS Lett 2020; 594:4012-4034. [PMID: 33015850 DOI: 10.1002/1873-3468.13947] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/27/2020] [Accepted: 09/21/2020] [Indexed: 12/13/2022]
Abstract
The ABCG2 protein has a key role in the transport of a wide range of structurally dissimilar endo- and xenobiotics in the human body, especially in the tissue barriers and the metabolizing or secreting organs. The human ABCG2 gene harbors a high number of polymorphisms and mutations, which may significantly modulate its expression and function. Recent high-resolution structural data, complemented with molecular dynamic simulations, may significantly help to understand intramolecular movements and substrate handling, as well as the effects of mutations on the membrane transporter function of ABCG2. As reviewed here, structural alterations may result not only in direct alterations in drug binding and transporter activity, but also in improper folding or problems in the carefully regulated process of trafficking, including vesicular transport, endocytosis, recycling, and degradation. Here, we also review the clinical importance of altered ABCG2 expression and function in general drug metabolism, cancer multidrug resistance, and impaired uric acid excretion, leading to gout.
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Affiliation(s)
- Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.,Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Tamás Hegedűs
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
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36
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Manzo G. Defined Mathematical Relationships Among Cancer Cells Suggest Modular Growth in Tumor Progression and Highlight Developmental Features Consistent With a Para-Embryonic Nature of Cancer. Front Cell Dev Biol 2020; 8:804. [PMID: 32984319 PMCID: PMC7484490 DOI: 10.3389/fcell.2020.00804] [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: 01/19/2020] [Accepted: 07/29/2020] [Indexed: 12/20/2022] Open
Abstract
Several similarities between the embryo development and the cancer process suggest the para-embryonic nature of tumors. Starting from an initial cancer stem cell (i-CSC) as a para-embryonic stem cell (p-ESC), a hierarchic sequence of CSCs (CSC1s, CSC2s, CSC3s) and non-CSCs [cancer progenitor cells (CPCs), cancer differentiated cells (CDCs)] would be generated, mimicking an ectopic rudimentary ontogenesis. Such a proposed heterogeneous cell hierarchy within the tumor structure would suggest a tumor growth model consistent with experimental data reported for mammary tumors. By tabulating the theoretical data according to this model, it is possible to identify defined mathematical relationships between cancer cells (CSCs and non-CSCs) that are surprisingly similar to experimental data. Moreover, starting from this model, it is possible to speculate that, during progression, tumor growth would occur in a modular way that recalls the propagation of tumor spheres in vitro. All these considerations favor a comparison among normal blastocysts (as in vitro embryos), initial avascular tumors (as in vivo abnormal blastocysts) and tumor spheres (as in vitro abnormal blastocysts). In conclusion, this work provides further support for the para-embryonic nature of the cancer process, as recently theorized.
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37
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Li C, Yang J, Liu C, Wang X, Zhang L. Long non-coding RNAs in hepatocellular carcinoma: Ordering of the complicated lncRNA regulatory network and novel strategies for HCC clinical diagnosis and treatment. Pharmacol Res 2020; 158:104848. [DOI: 10.1016/j.phrs.2020.104848] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 02/07/2023]
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38
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Singh AK, Verma A, Singh A, Arya RK, Maheshwari S, Chaturvedi P, Nengroo MA, Saini KK, Vishwakarma AL, Singh K, Sarkar J, Datta D. Salinomycin inhibits epigenetic modulator EZH2 to enhance death receptors in colon cancer stem cells. Epigenetics 2020; 16:144-161. [PMID: 32635858 DOI: 10.1080/15592294.2020.1789270] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Drug resistance is one of the trademark features of Cancer Stem Cells (CSCs). We and others have recently shown that paucity of functional death receptors (DR4/5) on the cell surface of tumour cells is one of the major reasons for drug resistance, but their involvement in the context of in CSCs is poorly understood. By harnessing CSC specific cytotoxic function of salinomycin, we discovered a critical role of epigenetic modulator EZH2 in regulating the expression of DRs in colon CSCs. Our unbiased proteome profiler array approach followed by ChIP analysis of salinomycin treated cells indicated that the expression of DRs, especially DR4 is epigenetically repressed in colon CSCs. Concurrently, EZH2 knockdown demonstrated increased expression of DR4/DR5, significant reduction of CSC phenotypes such as spheroid formation in-vitro and tumorigenic potential in-vivo in colon cancer. TCGA data analysis of human colon cancer clinical samples shows strong inverse correlation between EZH2 and DR4. Taken together, this study provides an insight about epigenetic regulation of DR4 in colon CSCs and advocates that drug-resistant colon cancer can be therapeutically targeted by combining TRAIL and small molecule EZH2 inhibitors.
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Affiliation(s)
- Anup Kumar Singh
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India
| | - Ayushi Verma
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India
| | - Akhilesh Singh
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India
| | - Rakesh Kumar Arya
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India
| | - Shrankhla Maheshwari
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.,Academy of Scientific and Innovative Research , New Delhi, India
| | - Priyank Chaturvedi
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India
| | - Mushtaq Ahmad Nengroo
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India
| | - Krishan Kumar Saini
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.,Academy of Scientific and Innovative Research , New Delhi, India
| | | | - Kavita Singh
- Electron Microscopy Unit, CSIR-CDRI , Lucknow, India
| | | | - Dipak Datta
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI) , Lucknow, India.,Academy of Scientific and Innovative Research , New Delhi, India
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39
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Shabo I, Svanvik J, Lindström A, Lechertier T, Trabulo S, Hulit J, Sparey T, Pawelek J. Roles of cell fusion, hybridization and polyploid cell formation in cancer metastasis. World J Clin Oncol 2020; 11:121-135. [PMID: 32257843 PMCID: PMC7103524 DOI: 10.5306/wjco.v11.i3.121] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/02/2020] [Accepted: 03/01/2020] [Indexed: 02/06/2023] Open
Abstract
Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE 171 77, Sweden
- Patient Area of Breast Cancer, Sarcoma and Endocrine Tumours, Theme Cancer, Karolinska University Hospital, Stockholm SE 171 76, Sweden
| | - Joar Svanvik
- The Transplant Institute, Sahlgrenska University Hospital, Gothenburg SE 413 45, Sweden
- Division of Surgery, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 83, Sweden
| | - Annelie Lindström
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping SE 581 85, Sweden
| | - Tanguy Lechertier
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Sara Trabulo
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - James Hulit
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - Tim Sparey
- Novintum Bioscience Ltd, London Bioscience Innovation Centre, London NW1 0NH, United Kingdom
| | - John Pawelek
- Department of Dermatology and the Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, United States
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40
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Lei Z, Tang X, Si A, Yang P, Wang L, Luo T, Guo G, Zhang Q, Cheng Z. microRNA-454 promotes liver tumor-initiating cell expansion by regulating SOCS6. Exp Cell Res 2020; 390:111955. [PMID: 32165166 DOI: 10.1016/j.yexcr.2020.111955] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 02/26/2020] [Accepted: 03/07/2020] [Indexed: 02/06/2023]
Abstract
Tumor-initiating cells (T-ICs) are involved in the tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. Herein, we find that miR-454 is upregulated in liver T-ICs and has an important function in liver T-ICs. Functional studies have revealed that knockdown of miR-454 inhibits liver T-IC self-renewal and tumorigenesis. Conversely, forced miR-454 expression promotes liver T-IC self-renewal and tumorigenesis. Mechanistically, we found that miR-454 downregulates SOCS6 expression in liver T-ICs. The correlation between miR-454 and SOCS6 is validated in human HCC tissues. Furthermore, HCC cells that overexpress miR-454 are resistant to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrates that miR-454 may predict sorafenib benefits in HCC patients. In conclusion, our findings reveal the crucial role of miR-454 in liver T-IC expansion and sorafenib response.
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Affiliation(s)
- Zhengqing Lei
- Hepato-pancreato-biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xuewu Tang
- Hepato-pancreato-biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Anfeng Si
- Department of Surgical Oncology, The Bayi Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | - Pinghua Yang
- Department of Minimally Invasive Surgery, The Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Lihong Wang
- Institute of Pathology and Southwest Hospital, Third Military Medical University (Army Medical University), And Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Tao Luo
- Institute of Pathology and Southwest Hospital, Third Military Medical University (Army Medical University), And Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Guangmeng Guo
- Hepato-pancreato-biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Qi Zhang
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Zhangjun Cheng
- Hepato-pancreato-biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
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41
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Kovacsics D, Brózik A, Tihanyi B, Matula Z, Borsy A, Mészáros N, Szabó E, Németh E, Fóthi Á, Zámbó B, Szüts D, Várady G, Orbán TI, Apáti Á, Sarkadi B. Precision-engineered reporter cell lines reveal ABCG2 regulation in live lung cancer cells. Biochem Pharmacol 2020; 175:113865. [PMID: 32142727 DOI: 10.1016/j.bcp.2020.113865] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/18/2020] [Indexed: 12/19/2022]
Abstract
Expression of the ABCG2 multidrug transporter is a marker of cancer stem cells and a predictor of recurrent malignant disease. Understanding how human ABCG2 expression is modulated by pharmacotherapy is crucial in guiding therapeutic recommendations and may aid rational drug development. Genome edited reporter cells are useful in investigating gene regulation and visualizing protein activity in live cells but require precise targeting to preserve native regulatory regions. Here, we describe a fluorescent reporter assay that allows the noninvasive assessment of ABCG2 regulation in human lung adenocarcinoma cells. Using CRISPR-Cas9 gene editing coupled with homology-directed repair, we targeted an EGFP coding sequence to the translational start site of ABCG2, generating ABCG2 knock-out and in situ tagged ABCG2 reporter cells. Using the engineered cell lines, we show that ABCG2 is upregulated by a number of anti-cancer medications, HDAC inhibitors, hypoxia-mimicking agents and glucocorticoids, supporting a model in which ABCG2 is under the control of a general stress response. To our knowledge, this is the first description of a fluorescent reporter assay system designed to follow the endogenous regulation of a human ABC transporter in live cells. The information gained may guide therapy recommendations and aid rational drug design.
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Affiliation(s)
- Daniella Kovacsics
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Anna Brózik
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Borbála Tihanyi
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Zsolt Matula
- South-Pest Hospital Centre, National Institute of Hematology and Infectious Diseases, Laboratory of Molecular and Cytogenetics, Budapest, Hungary
| | - Adrienn Borsy
- South-Pest Hospital Centre, National Institute of Hematology and Infectious Diseases, Laboratory of Molecular and Cytogenetics, Budapest, Hungary
| | - Nikolett Mészáros
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Edit Szabó
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Eszter Németh
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Ábel Fóthi
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Boglárka Zámbó
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Dávid Szüts
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - György Várady
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Tamás I Orbán
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Ágota Apáti
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Balázs Sarkadi
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary.
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Yang Y, Klionsky DJ. Autophagy and disease: unanswered questions. Cell Death Differ 2020; 27:858-871. [PMID: 31900427 PMCID: PMC7206137 DOI: 10.1038/s41418-019-0480-9] [Citation(s) in RCA: 270] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/03/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022] Open
Abstract
Autophagy is a process in which intracellular components and dysfunctional organelles are delivered to the lysosome for degradation and recycling. Autophagy has various connections to a large number of human diseases, as its functions are essential for cell survival, bioenergetic homeostasis, organism development, and cell death regulation. In the past two decades, substantial effort has been made to identify the roles of autophagy in tumor suppression and promotion, neurodegenerative disorders, and other pathophysiologies. This review summarizes the current advances and discusses the unanswered questions in understanding the involvement of autophagy in pathogenic mechanisms of disease, primarily focusing on cancer and neurodegenerative diseases.
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Affiliation(s)
- Ying Yang
- Department of Molecular, Cellular, and Developmental Biology, and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Daniel J Klionsky
- Department of Molecular, Cellular, and Developmental Biology, and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
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Saleem MZ, Nisar MA, Alshwmi M, Din SRU, Gamallat Y, Khan M, Ma T. Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells. Onco Targets Ther 2020; 13:435-450. [PMID: 32021288 PMCID: PMC6970270 DOI: 10.2147/ott.s228702] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 12/10/2019] [Indexed: 12/19/2022] Open
Abstract
Purpose Breast cancer is the most common malignancy among women across the globe. Despite concerted efforts to improve the prevailing treatment modalities, the overall prognosis of breast cancer remains unsatisfactory. Recently, antiproliferative activity of Brevilin A (Brv-A), a sesquiterpene lactone compound of Centipeda minima, has been unveiled in various cancer types. Here, we have explored anticancer activity of Brv-A in MCF-7 breast carcinoma cells by targeting various pathways. Materials and Methods Cell proliferation rate was determined by CCK-8 and clonogenic assay. Cellular morphological changes were observed under phase contrast microscope while calcein-AM and PI was used for live/dead assay. Cell cycle assay was performed by flow cytometry. Apoptotic cell percentage was determined by Hoechst 33258 staining and flow cytometric analysis. ROS generation and mitochondrial membrane potential were measured using commercially available kits while protein expression was measured by Western blotting. Results In our study, Brv-A exerted antiproliferative effect through mitotic arrest at G2/M phase of cell cycle and induced apoptosis in MCF-7 cells in a dose-dependent manner. Induction of apoptosis by Brv-A was found to be associated with ROS generation by targeting NOX2 and NOX3, mitochondrial dysfunction (MMP dissipation and Bcl-2 family proteins modulation), DNA fragmentation, JNK and p38 MAPK activation, endoplasmic reticulum (ER) stress by increasing Bip/GRP78, ATF4 and CHOP protein expressions and inhibition of STAT3 activation via decreased phosphorylation of JAK2 and SRC. Pretreatment of NAC, a ROS scavenger, partially reversed the aforesaid cellular events indicating ROS generation as the primary event to modulate cellular targets for induction of apoptosis. Besides, Brv-A has also been documented for inhibition of cell migration via decrease in COX-2 and MMP-2 expression. Conclusion Taken together, Brv-A induces G2/M phase arrest, ROS-dependent apoptosis, ER stress, mitochondrial dysfunction and inhibits STAT3 activation in MCF-7 cells signifying it to be one of the potential anticancer therapeutics in future.
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Affiliation(s)
- Muhammad Zubair Saleem
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, People's Republic of China
| | - Muhammad Azhar Nisar
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, People's Republic of China
| | - Mohammed Alshwmi
- Department of Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liaoning 116044, People's Republic of China
| | - Syed Riaz Ud Din
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, People's Republic of China
| | - Yaser Gamallat
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, People's Republic of China
| | - Muhammad Khan
- Department of Zoology, University of the Punjab, Lahore, Punjab 54590, Pakistan
| | - Tonghui Ma
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, People's Republic of China
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44
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Han T, Zhang Y, Yang X, Han L, Li H, Chen T, Zheng Z. miR-552 Regulates Liver Tumor-Initiating Cell Expansion and Sorafenib Resistance. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 19:1073-1085. [PMID: 32044726 PMCID: PMC7015836 DOI: 10.1016/j.omtn.2019.12.043] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/24/2019] [Accepted: 12/09/2019] [Indexed: 01/27/2023]
Abstract
MicroRNAs (miRNAs) are involved in tumorigenesis, progression, recurrence, and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that microRNA (miR)-552 is upregulated in HCC tissues and has an important function in liver tumor-initiating cells (T-ICs). Functional studies revealed that a forced expression of miR-552 promotes liver T-IC self-renewal and tumorigenesis. Conversely, miR-552 knockdown inhibits liver T-IC self-renewal and tumorigenesis. Mechanistically, miR-552 downregulates phosphatase and tensin homolog (PTEN) via its mRNA 3' UTR and activates protein kinase B (AKT) phosphorylation. Our clinical investigations elucidated the prognostic value of miR-552 in HCC patients. Furthermore, miR-552 expression determines the responses of hepatoma cells to sorafenib treatment. The analysis of patient cohorts and patient-derived xenografts (PDXs) further demonstrated that miR-552 may predict sorafenib benefits in HCC patients. In conclusion, our findings revealed the crucial role of the miR-552 in liver T-IC expansion and sorafenib response, rendering miR-552 an optimal target for the prevention and intervention in HCC.
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Affiliation(s)
- Tao Han
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China; Department of Oncology, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, Liaoning Province, China
| | - Yue Zhang
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China; Graduate School, Jinzhou Medical University, Jinzhou, 121000 Liaoning Province, China
| | - Xiaodan Yang
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China
| | - Lei Han
- Department of Hepatobiliary Surgery, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China
| | - Hengyu Li
- Department of Breast and Thyroid Surgery, First Affiliated Hospital of Second Military Medical University, 200433 Shanghai, China.
| | - Tingsong Chen
- Department of Cancer Intervention, Shanghai Seventh People's Hospital, 200001 Shanghai, China.
| | - Zhendong Zheng
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China.
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Song S, Sun K, Dong J, Zhao Y, Liu F, Liu H, Sha Z, Mao J, Ding G, Guo W, Fu Z. microRNA-29a regulates liver tumor-initiating cells expansion via Bcl-2 pathway. Exp Cell Res 2019; 387:111781. [PMID: 31857112 DOI: 10.1016/j.yexcr.2019.111781] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 12/12/2019] [Accepted: 12/13/2019] [Indexed: 12/26/2022]
Abstract
MicroRNAs (miRNAs) participate in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that miR-29a is downregulated in tumor-initiating cells (T-ICs) and has an important function in liver T-ICs. Functional studies revealed that miR-29a knockdown promotes liver T-ICs self-renewal and tumorigenesis. Conversely, a forced miR-29a expression inhibits liver T-ICs self-renewal and tumorigenesis. Mechanistically, we find that miR-29a downregulates Bcl-2 via binding its mRNA 3'UTR in liver T-ICs. The correlation between miR-29a and Bcl-2 is validated in human HCC tissues. Furthermore, the miR-29a expression determines the responses of hepatoma cells to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-29a high patients are more sensitive to sorafenib treatment. In conclusion, our findings revealed the crucial role of the miR-29a in liver T-ICs expansion and sorafenib response, rendering miR-29a as an optimal target for the prevention and intervention of HCC.
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Affiliation(s)
- Shaohua Song
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Keyan Sun
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Junfeng Dong
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Yuanyu Zhao
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Fang Liu
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Hao Liu
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Zhilin Sha
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Jiaxi Mao
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Guoshan Ding
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Wenyuan Guo
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
| | - Zhiren Fu
- Organ Transplantation Center, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
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Si A, Wang L, Miao K, Zhang R, Ji H, Lei Z, Cheng Z, Fang X, Hao B. miR-219 regulates liver cancer stem cell expansion via E-cadherin pathway. Cell Cycle 2019; 18:3550-3561. [PMID: 31724462 PMCID: PMC6927721 DOI: 10.1080/15384101.2019.1691762] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 10/03/2019] [Accepted: 10/06/2019] [Indexed: 02/06/2023] Open
Abstract
Liver cancer stem cells contribute to tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liverCSCs is not fully understood yet. Here we show that miR-219 is upregulated in liver CSCs. Knockdown of miR-219 attenuates the self-renewal and tumorigenicity of liver CSCs. Conversely, miR-219 overexpressing enhances the self-renewal and tumorigenicity of liver CSCs.Mechanistically,miR-219 downregulates E-cadherin via itsmRNA 3'UTR in liver CSCs. The correlation between miR-219 and E-cadherin is validated in human HCC tissues. Furthermore, the miR-219 expression determines the responses of hepatoma cells to sorafenib treatment. Our findings indicate that miR-219 plays a critical role in liver CSCs expansion and sorafenib response, rendering miR-219 as an optimal target for the prevention and intervention of HCC.Abbreviations: HCC: Hepatocellular carcinoma; CSCs: cancer stem cells; DMEM: Dulbecco's modified Eagle's medium; FBS: fetal bovine serum; OS: overall survival.
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Affiliation(s)
- Anfeng Si
- Department of Surgical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Longqi Wang
- Department of General Surgery I, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Kun Miao
- Oncology Department Ward, Tianchang People’s Hospital, Anhui, China
| | - Rongrong Zhang
- Department of General Surgery III, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Huiyu Ji
- Department of Surgical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Zhengqing Lei
- Department of General Surgery, the Affiliated Zhongda Hospital, Southeast University, Nanjing, China
| | - Zhangjun Cheng
- Department of General Surgery, the Affiliated Zhongda Hospital, Southeast University, Nanjing, China
| | - Xiangchun Fang
- Department of Surgical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Baobing Hao
- Department of Surgical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
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Chien CH, Chuang JY, Yang ST, Yang WB, Chen PY, Hsu TI, Huang CY, Lo WL, Yang KY, Liu MS, Chu JM, Chung PH, Liu JJ, Chou SW, Chen SH, Chang KY. Enrichment of superoxide dismutase 2 in glioblastoma confers to acquisition of temozolomide resistance that is associated with tumor-initiating cell subsets. J Biomed Sci 2019; 26:77. [PMID: 31629402 PMCID: PMC6800988 DOI: 10.1186/s12929-019-0565-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 09/10/2019] [Indexed: 12/13/2022] Open
Abstract
Background Intratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment. Our goal is to identify the key factor in the process by which cells develop temozolomide (TMZ) resistance. Methods Resistant cell lines derived from U87MG and A172 were established through long-term co-incubation of TMZ. Primary tumors obtained from patients were maintained as patient-derived xenograft for studies of tumor-initating cell (TIC) features. The cell manifestations were assessed in the gene modulated cells for relevance to drug resistance. Results Among the mitochondria-related genes in the gene expression databases, superoxide dismutase 2 (SOD2) was a significant factor in resistance and patient survival. SOD2 in the resistant cells functionally determined the cell fate by limiting TMZ-stimulated superoxide reaction and cleavage of caspase-3. Genetic inhibition of the protein led to retrieval of drug effect in mouse study. SOD2 was also associated with the TIC features, which enriched in the resistant cells. The CD133+ specific subsets in the resistant cells exhibited superior superoxide regulation and the SOD2-related caspase-3 reaction. Experiments applying SOD2 modulation showed a positive correlation between the TIC features and the protein expression. Finally, co-treatment with TMZ and the SOD inhibitor sodium diethyldithiocarbamate trihydrate in xenograft mouse models with the TMZ-resistant primary tumor resulted in lower tumor proliferation, longer survival, and less CD133, Bmi-1, and SOD2 expression. Conclusion SOD2 plays crucial roles in the tumor-initiating features that are related to TMZ resistance. Inhibition of the protein is a potential therapeutic strategy that can be used to enhance the effects of chemotherapy. Graphical abstract ![]()
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Affiliation(s)
- Chia-Hung Chien
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Jian-Ying Chuang
- Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.,The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shun-Tai Yang
- Division of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Wen-Bin Yang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pin-Yuan Chen
- Department of Neurosurgery, Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
| | - Tsung-I Hsu
- Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan
| | - Chih-Yuan Huang
- Division of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Wei-Lun Lo
- Division of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ka-Yen Yang
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Sheng Liu
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan.,Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan
| | - Jui-Mei Chu
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Pei-Hsuan Chung
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Jr-Jiun Liu
- Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.,The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shao-Wen Chou
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan
| | - Shang-Hung Chen
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan.,Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kwang-Yu Chang
- National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan. .,Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Bakhshi M, Asadi J, Ebrahimi M, Moradi AV, Hajimoradi M. Increased expression of miR-146a, miR-10b, and miR-21 in cancer stem-like gastro-spheres. J Cell Biochem 2019; 120:16589-16599. [PMID: 31095782 DOI: 10.1002/jcb.28918] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 04/10/2019] [Accepted: 04/11/2019] [Indexed: 12/01/2023]
Abstract
BACKGROUND Gastric cancer remains one of the leading causes of cancer-associated mortalities globally. Accumulating evidence support the presence of gastric cancer stem cells (CSCs) and their role in the pathogenesis and therapeutic challenges of gastric cancer. MicroRNAs (miRNAs) may be influenced by the cellular differentiative state and as critical regulators of the cellular fate in development and cancer, can modulate the behavior of CSCs too. Here, we aimed to investigate the expression relevance of three prognostic miRNAs (miR-21, miR-10b, and miR-146a) in CSCs of AGS and MKN-45 gastric cancer cell lines. METHODS Serial sphere-forming assay in serum-free culture medium was used to enrich the cellular population with stem-like properties. Gastro-spheres were characterized by evaluating the stemness gene expression, clonogenicity, and resistance to docetaxel and cisplatin in comparison with their parental cells. The expression level of miRNAs in gastro-spheres and their parental cells was measured using quantitative reverse transcription polymerase chain reaction. RESULTS Gastro-spheres from both cell lines exhibit stem-like properties: upregulated stemness associated genes (P < 0.05), more colonogenicity and more resistance to docetaxel (P < 0.05). MKN-45 gastro-spheres exhibited upregulated expression of miR-21 (1.8-folds), miR-10b (1.34-folds) and miR-146a (4.8-folds; P < 0.05) compared with the parental cells. AGS-derived gastro-spheres showed upregulation of miR-21 (4.7-folds; P < 0.01), miR-10b (15.2-folds; P < 0.001) and miR-146a (39.3-folds; P < 0.05). CONCLUSION Our data exhibited upregulation of miR-21, miR-10b, and miR-146a in the stem-like gastro-spheres; however; their function in gastric CSCs remains to be verified by further experiments.
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Affiliation(s)
- Mahdieh Bakhshi
- Department of Molecular Medicine, Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran
| | - Jahanbakhsh Asadi
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Hematopoietic and Cancer Stem Cell Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran, Iran
| | - Abdol-Vahab Moradi
- Department of Molecular Medicine, Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran
| | - Monireh Hajimoradi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Zhang J, Cao Z, Yang G, You L, Zhang T, Zhao Y. MicroRNA-27a (miR-27a) in Solid Tumors: A Review Based on Mechanisms and Clinical Observations. Front Oncol 2019; 9:893. [PMID: 31572683 PMCID: PMC6751266 DOI: 10.3389/fonc.2019.00893] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 08/27/2019] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are a family of highly conserved, non-coding single-stranded RNAs transcribed as ~70 nucleotide precursors to an 18–22 nucleotide product (1). miRNAs can silence their homologous target genes at the post-transcriptional level, and these genes have been revealed to play an important role in tumorigenesis, invasion and metastasis (2). MicroRNA-27a (miR-27a), transcripted by miR-27a gene, has proved to implicate with many kinds of solid tumors, showing potential as a useful biomarker or drug target for clinical application. However, even though miR-27a has been reported in many cancers, the mechanism and signal pathways of miR-27 in oncogenesis, invasion, and metastasis are still obscure. Moreover, recent studies show that miR-27a pays an important role in epithelial-mesenchymal-transition, regulating tumor immune response, and chemoresistance. In this review, we summarize the current literature, demonstrate the established link between miR-27a and tumorigenesis, and focus on recently identified mechanisms. The review also aims to demonstrate the potential of miR-27a as a diagnostic and/or prognostic biomarker in solid tumors and to discuss the possibilities of targeted therapy and drug design.
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Affiliation(s)
- Jingcheng Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhe Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Yang F, Cui P, Lu Y, Zhang X. Requirement of the transcription factor YB-1 for maintaining the stemness of cancer stem cells and reverting differentiated cancer cells into cancer stem cells. Stem Cell Res Ther 2019; 10:233. [PMID: 31375149 PMCID: PMC6679460 DOI: 10.1186/s13287-019-1360-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 07/12/2019] [Accepted: 07/24/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Cancer stem cells always express high levels of stemness-associated transcription factors to maintain their features. However, the regulatory mechanism of the stemness of cancer stem cells mediated by transcription factors has not been extensively explored. METHODS The YB-1 gene in cancer stem cells was knocked out by the CRISPR/Cas9 system. The YB-1 knockout cancer stem cells were transfected with a vector expressing YB-1 to rescue YB-1, and then the cell proliferation, cell cycle, apoptosis, and stemness, as well as tumorigenesis in nude mice, were assessed to examine the effect of YB-1 in cancer stem cells. The target genes of YB-1 were confirmed by CHIP-seq. The totipotency or pluripotency of differentiated cancer stem cells were detected by tumorsphere formation assay and quantitative real-time PCR. RESULTS The deletion of YB-1 gene inhibited the proliferation of breast cancer stem cells and melanoma stem cells, leading to cell cycle arrest and apoptosis, and induced irreversible differentiation of cancer stem cells. The tumorigenicity ability of YB-1-deleted cancer stem cells was significantly reduced in vitro and in vivo. The results of ChIP-seq showed that YB-1 maintained the stemness of cancer stem cells by promoting the expressions of stemness-associated genes (FZD-1, p21, GLP-1, GINS1, and Notch2). Furthermore, simultaneous expressions of YB-1 and the other four (SOX2, POU3F2, OCT-4, and OLIG1) or five (SOX2, SALL2, OCT-4, POU3F2, and Bmi-1) transcription factors in YB-1 knockout cancer stem cells restored the stemness of YB-1 knockout cancer stem cells. CONCLUSIONS Our study indicated that YB-1 was required for maintaining the stemness of cancer stem cells and reverting the differentiated tumor cells into cancer stem cells.
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Affiliation(s)
- Fan Yang
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Pei Cui
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Yu Lu
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Xiaobo Zhang
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China.
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