|
1
|
Chen W, Wang YJ. Multifaceted roles of OCT4 in tumor microenvironment: biology and therapeutic implications. Oncogene 2025; 44:1213-1229. [PMID: 40229384 DOI: 10.1038/s41388-025-03408-x] [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: 09/16/2024] [Revised: 03/28/2025] [Accepted: 04/04/2025] [Indexed: 04/16/2025]
Abstract
OCT4 (Octamer-binding transcription factor 4, encoded by the POU5F1 gene) is a master transcription factor for maintaining the self-renewal and pluripotency of pluripotent stem cells, as well as a pioneer factor regulating epigenetics-driven cell reprogramming and cell fate conversion. It is also detected in a variety of cancer tissues and particularly in a small subpopulation of cancer cells known as cancer stem cells (CSCs). Accumulating evidence has revealed that CSCs are a dynamic population, exhibiting shift between multipotency and differentiation states, or quiescence and proliferation states. Such cellular plasticity of CSCs is profoundly influenced by dynamic interplay between CSCs and the tumor microenvironment (TME). Here, we review recent evidence showing that OCT4 expressed in CSCs plays a multifaceted role in shaping the TME by interacting with the cellular TME components, including cancer-associated fibroblasts, tumor endothelial cells, tumor-infiltrating immune cells, as well as the non-cellular TME components, such as extracellular matrix (ECM), metabolites, soluble factors (e.g., growth factors, cytokines and chemokines), and intra-tumoral microbiota. Together, OCT4 regulates crucial processes encompassing ECM remodeling, epithelial-mesenchymal transition, metabolic reprogramming, angiogenesis, and immune responses. The complex and bidirectional interactions between OCT4-expressing CSCs and the TME create a supportive niche for tumor growth, invasion, and resistance to therapy. Better understanding OCT4's roles in such interactions can provide deeper insights into potential therapeutic strategies and targets for disrupting the supportive environment of tumors. The emerging therapies targeting OCT4 in CSCs might hold promise to resensitize therapeutic-resistant cancer cells, and to eradicate all cancer cells when combined with other therapies targeting the bulk of differentiated cancer cells as well as the TME.
Collapse
Affiliation(s)
- Wenjie Chen
- Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ying-Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
2
|
Khosravi Z, Mirzaeian L, Ghorbanian MT, Rostami F. Lovastatin Combination Therapy Increases the Survival and Proliferation of Rat Bone Marrow-Derived Mesenchymal Stem Cells Against the Inflammatory Activity of Lipopolysaccharide. Cell Biochem Biophys 2024; 82:2585-2595. [PMID: 38963603 DOI: 10.1007/s12013-024-01372-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] [Accepted: 06/16/2024] [Indexed: 07/05/2024]
Abstract
Oxidative stress hurts the survival of transplanted mesenchymal stem cells (MSCs). Lipopolysaccharide (LPS) preconditioning inhibits apoptotic death in MSCs. Also, Lovastatin's protective effect was reported on MSCs. Here, we investigated the potential of LPS and Lovastatin combination therapy on the survival and proliferation of MSCs. MSCs harvested from adult rats (240-260 g) femur and tibia bone marrow. Third passage MSCs were divided into 6 groups control group, LPS, LPS + Lovastatin (10 and 15 µM), and Lovastatin (10 and 15 µM). Cell survival and proliferation were assessed using an MTT assay 24 h after LPS, Lovastatin, or LPS + Lovastatin treatment. Also, Malondialdehyde (MDA) as a lipid peroxidation marker and antioxidant enzymes such as Glutathione peroxidase (GPX) and Superoxide dismutase (SOD) activity levels evaluated. Finally, the expression level of tumor protein P53 (P53) and octamer-binding transcription factor 4 (OCT4) genes were measured by qRT-PCR test. Lovastatin 10 μM potentiated proliferation and survival of MSCs. It can increase the activity of GPX and SOD. 10 µM Lovastatin could not affect MDA amounts but decreased the expression levels of P53 and Oct4 significantly. Nevertheless, treatment with LPS reduced the survival and proliferation of MSCs, along with a significant reduction in GPX activity. LPS + Lovastatin could increase SOD activity, however, GPX enzyme activity and MSCs proliferation did not change so, and it was not effective. We propose Lovastatin at the dose of 10 µM as a suitable combination agent to increase the survival and proliferation of MSCs in oxidative stress conditions.
Collapse
Affiliation(s)
- Ziba Khosravi
- Department of Cellular and Molecular Biology, School of Biology, Damghan University, Damghan, Iran
| | - Leila Mirzaeian
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
| | | | - Farzaneh Rostami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| |
Collapse
|
|
3
|
Gadwal A, Purohit P, Khokhar M, Vishnoi JR, Pareek P, Choudhary R, Elhence P, Banerjee M, Sharma P. GALNT14 in association with GDF-15 promotes stemness and drug resistance through β-catenin signalling pathway in breast cancer. Mol Biol Rep 2024; 51:691. [PMID: 38796671 DOI: 10.1007/s11033-024-09645-9] [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: 03/11/2024] [Accepted: 05/16/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND Altered glycosylation plays a role in carcinogenesis. GALNT14 promotes cancer stem-like properties and drug resistance. GDF-15 is known to induces drug resistance and stemness markers for maintenance of breast cancer (BC) stem-like cell state. Currently there is lack of data on association of GDF-15 and GALNTs. In this study, the expression and interaction of GALNT14 and GDF-15 with stemness (OCT4 and SOX2) and drug resistance (ABCC5) markers were evaluated in BC. METHODS We investigated tumour tissue from 30 BC patients and adjacent non-tumour tissues. Expression of serum GALNT14 from BC patients and matched healthy controls was evaluated. Expression of GALNT14, GDF-15, OCT4, SOX2, ABCC5, and β-catenin in BC tissue was determined by RT-PCR. Knockdown of GALNT14 and GDF-15 in the MCF-7 cell line was done through siRNA, gene expression and protein expression of β-catenin by western blot were determined. RESULTS A significant increase in the expression of GALNT14, GDF-15, OCT4, SOX2, ABCC5, and β-catenin was observed in BC tumour tissues compared to adjacent non-tumour tissues. The serum level of GALNT14 was significantly high in BC patients (80.7 ± 65.3 pg/ml) compared to healthy controls (12.2 ± 9.12 pg/ml) (p < 0.000). To further analyse the signalling pathway involved in BC stemness and drug resistance, GALNT14 and GDF-15 were knocked down in the MCF-7 cell line, and it was observed that after knockdown, the expression level of OCT4, SOX2, ABCC5, and β-catenin was decreased, and co-knockdown with GALNT14 and GDF-15 further decreased the expression of genes. CONCLUSION It can be concluded that GALNT14, in association with GDF-15, promotes stemness and intrinsic drug resistance in BC, possibly through the β-catenin signalling pathway.
Collapse
Affiliation(s)
- Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India.
| | - Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
| | - Jeewan Ram Vishnoi
- Department of Oncosurgery, All India Institute of Medical Sciences, Jodhpur, India
| | - Puneet Pareek
- Department of Radiation Oncology, All India Institute of Medical Sciences, Jodhpur, India
| | - Ramkaran Choudhary
- Department of General Surgery, All India Institute of Medical Sciences, Jodhpur, India
| | - Poonam Elhence
- Department of Pathology, All India Institute of Medical Sciences, Jodhpur, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
| |
Collapse
|
|
4
|
Dimitriou NM, Demirag E, Strati K, Mitsis GD. A calibration and uncertainty quantification analysis of classical, fractional and multiscale logistic models of tumour growth. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2024; 243:107920. [PMID: 37976612 DOI: 10.1016/j.cmpb.2023.107920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 10/27/2023] [Accepted: 11/05/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND AND OBJECTIVE The validation of mathematical models of tumour growth is frequently hampered by the lack of sufficient experimental data, resulting in qualitative rather than quantitative studies. Recent approaches to this problem have attempted to extract information about tumour growth by integrating multiscale experimental measurements, such as longitudinal cell counts and gene expression data. In the present study, we investigated the performance of several mathematical models of tumour growth, including classical logistic, fractional and novel multiscale models, in terms of quantifying in-vitro tumour growth in the presence and absence of therapy. We further examined the effect of genes associated with changes in chemosensitivity in cell death rates. METHODS The multiscale expansion of logistic growth models was performed by coupling gene expression profiles to the cell death rates. State-of-the-art Bayesian inference, likelihood maximisation and uncertainty quantification techniques allowed a thorough evaluation of model performance. RESULTS The results suggest that the classical single-cell population model (SCPM) was the best fit for the untreated and low-dose treatment conditions, while the multiscale model with a cell death rate symmetric with the expression profile of OCT4 (Sym-SCPM) yielded the best fit for the high-dose treatment data. Further identifiability analysis showed that the multiscale model was both structurally and practically identifiable under the condition of known OCT4 expression profiles. CONCLUSIONS Overall, the present study demonstrates that model performance can be improved by incorporating multiscale measurements of tumour growth when high-dose treatment is involved.
Collapse
Affiliation(s)
| | - Ece Demirag
- Department of Biological Sciences, University of Cyprus, Nicosia, 2109, Cyprus
| | - Katerina Strati
- Department of Biological Sciences, University of Cyprus, Nicosia, 2109, Cyprus
| | - Georgios D Mitsis
- Department of Bioengineering, McGill University, Montreal, H3A 0E9, QC, Canada.
| |
Collapse
|
|
5
|
Singh D, Biswas D, Tewari M, Kar AG, Ansari MA, Singh S, Narayan G. Clinical Significance of Overexpression of Oct4 in Advanced Stage Gallbladder Carcinoma. J Gastrointest Cancer 2023; 54:1231-1239. [PMID: 36705780 DOI: 10.1007/s12029-023-00913-8] [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: 01/22/2023] [Indexed: 01/28/2023]
Abstract
BACKGROUND Oct4 has critical role in maintaining pluripotency, proliferative potential, and self-renewal capacity in embryonic stem and germ cells. Although Oct4 has been shown to be upregulated in many cancers, its clinical significance in gallbladder carcinoma is poorly understood. METHODS We studied the expression profile of Oct4 in 61 GBC and 30 chronic cholecystitis (as control) using real time RT-PCR, western blotting, and immunohistochemistry. The expression data was correlated with clinico-pathological parameters. The diagnostic utility was assessed through ROC curve, and prognostic value was analyzed by Kaplan-Meier method. RESULTS Oct4 was significantly upregulated at mRNA as well as protein levels. The higher mRNA expression shows significant association with late stage, late T stage, and higher grade of tumor. A significant positive correlation was also observed with stage, T stage, and tumor grade. Sum score analysis of protein expression shows positive correlation with stage and the presence or absence of gallstone in tumor samples. The ROC curve analysis revealed the moderate diagnostic potential of Oct4. Kaplan-Meier analysis showed that patients having higher expression of Oct4 were having low mean survival compared with the patients with lower Oct4 expression. CONCLUSION In conclusion, our data suggests that higher expression of Oct4 may serve as potential biological indicator for tumor aggressiveness and poor prognosis of GBC.
Collapse
Affiliation(s)
- Deepika Singh
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
- Department of Radiation Oncology, The Ohio State University, Columbus, 43210, USA
| | - Dipanjan Biswas
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
- Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, 400012, India
| | - Mallika Tewari
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Amrita Ghosh Kar
- Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Mumtaz Ahmad Ansari
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India
| | - Sunita Singh
- Department of Zoology, Banaras Hindu University, Mahila Mahavidyalaya, Varanasi, 221005, India
| | - Gopeshwar Narayan
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
| |
Collapse
|
|
6
|
Panayiotou T, Eftychiou M, Patera E, Promponas VJ, Strati K. A paradigm for post-embryonic Oct4 re-expression: E7-induced hydroxymethylation regulates Oct4 expression in cervical cancer. J Med Virol 2023; 95:e29264. [PMID: 38054553 DOI: 10.1002/jmv.29264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 11/08/2023] [Accepted: 11/11/2023] [Indexed: 12/07/2023]
Abstract
The Octamer-binding transcription factor-4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post-embryonic re-expression is inadequately understood. In cervical cancer, Oct4 expression is higher in human papillomavirus (HPV)-related than HPV-unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4-transcriptional output and Oct4-related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4-protein interactions in cervical cancer cells via computational analyses and Mass Spectrometry and reveal that Methyl-binding proteins (MBD2 and MBD3), are determinants of Oct4-driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re-expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate Oct4 re-expression and global transcriptional patterns by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis.
Collapse
Affiliation(s)
| | - Marios Eftychiou
- Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
- Leuven Statistics Research Centre (LStat), KU Leuven, Leuven, Belgium
| | - Eleutherios Patera
- Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
| | | | - Katerina Strati
- Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
| |
Collapse
|
|
7
|
Justo-Garrido M, López-Saavedra A, Alcaraz N, Cortés-González CC, Oñate-Ocaña LF, Caro-Sánchez CHS, Castro-Hernández C, Arriaga-Canon C, Díaz-Chávez J, Herrera LA. Association of SLC12A1 and GLUR4 Ion Transporters with Neoadjuvant Chemoresistance in Luminal Locally Advanced Breast Cancer. Int J Mol Sci 2023; 24:16104. [PMID: 38003293 PMCID: PMC10670992 DOI: 10.3390/ijms242216104] [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: 09/29/2023] [Revised: 10/24/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
Chemoresistance to standard neoadjuvant treatment commonly occurs in locally advanced breast cancer, particularly in the luminal subtype, which is hormone receptor-positive and represents the most common subtype of breast cancer associated with the worst outcomes. Identifying the genes associated with chemoresistance is crucial for understanding the underlying mechanisms and discovering effective treatments. In this study, we aimed to identify genes linked to neoadjuvant chemotherapy resistance in 62 retrospectively included patients with luminal breast cancer. Whole RNA sequencing of 12 patient biopsies revealed 269 differentially expressed genes in chemoresistant patients. We further validated eight highly correlated genes associated with resistance. Among these, solute carrier family 12 member 1 (SLC12A1) and glutamate ionotropic AMPA type subunit 4 (GRIA4), both implicated in ion transport, showed the strongest association with chemoresistance. Notably, SLC12A1 expression was downregulated, while protein levels of glutamate receptor 4 (GLUR4), encoded by GRIA4, were elevated in patients with a worse prognosis. Our results suggest a potential link between SLC12A1 gene expression and GLUR4 protein levels with chemoresistance in luminal breast cancer. In particular, GLUR4 protein could serve as a potential target for drug intervention to overcome chemoresistance.
Collapse
Affiliation(s)
- Montserrat Justo-Garrido
- Cancer Research Unit, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)-National Institute of Cancerology, San Fernando Av #22, XVI Section, Mexico City 14080, Mexico; (M.J.-G.); (A.L.-S.); (C.C.C.-G.); (C.C.-H.); (C.A.-C.)
| | - Alejandro López-Saavedra
- Cancer Research Unit, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)-National Institute of Cancerology, San Fernando Av #22, XVI Section, Mexico City 14080, Mexico; (M.J.-G.); (A.L.-S.); (C.C.C.-G.); (C.C.-H.); (C.A.-C.)
| | - Nicolás Alcaraz
- The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark;
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark
| | - Carlo C. Cortés-González
- Cancer Research Unit, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)-National Institute of Cancerology, San Fernando Av #22, XVI Section, Mexico City 14080, Mexico; (M.J.-G.); (A.L.-S.); (C.C.C.-G.); (C.C.-H.); (C.A.-C.)
| | - Luis F. Oñate-Ocaña
- Department of Gastroenterology, National Cancer Institute (INCan), Tlalpan, Mexico City 14080, Mexico;
| | | | - Clementina Castro-Hernández
- Cancer Research Unit, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)-National Institute of Cancerology, San Fernando Av #22, XVI Section, Mexico City 14080, Mexico; (M.J.-G.); (A.L.-S.); (C.C.C.-G.); (C.C.-H.); (C.A.-C.)
| | - Cristian Arriaga-Canon
- Cancer Research Unit, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)-National Institute of Cancerology, San Fernando Av #22, XVI Section, Mexico City 14080, Mexico; (M.J.-G.); (A.L.-S.); (C.C.C.-G.); (C.C.-H.); (C.A.-C.)
| | - José Díaz-Chávez
- Cancer Research Unit, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)-National Institute of Cancerology, San Fernando Av #22, XVI Section, Mexico City 14080, Mexico; (M.J.-G.); (A.L.-S.); (C.C.C.-G.); (C.C.-H.); (C.A.-C.)
| | - Luis A. Herrera
- Cancer Research Unit, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)-National Institute of Cancerology, San Fernando Av #22, XVI Section, Mexico City 14080, Mexico; (M.J.-G.); (A.L.-S.); (C.C.C.-G.); (C.C.-H.); (C.A.-C.)
- School of Medicine and Health Sciences-Tecnológico de Monterrey, Mexico City 14380, Mexico
| |
Collapse
|
|
8
|
Fleifel D, Cook JG. G1 Dynamics at the Crossroads of Pluripotency and Cancer. Cancers (Basel) 2023; 15:4559. [PMID: 37760529 PMCID: PMC10526231 DOI: 10.3390/cancers15184559] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
G1 cell cycle phase dynamics are regulated by intricate networks involving cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors, which control G1 progression and ensure proper cell cycle transitions. Moreover, adequate origin licensing in G1 phase, the first committed step of DNA replication in the subsequent S phase, is essential to maintain genome integrity. In this review, we highlight the intriguing parallels and disparities in G1 dynamics between stem cells and cancer cells, focusing on their regulatory mechanisms and functional outcomes. Notably, SOX2, OCT4, KLF4, and the pluripotency reprogramming facilitator c-MYC, known for their role in establishing and maintaining stem cell pluripotency, are also aberrantly expressed in certain cancer cells. In this review, we discuss recent advances in understanding the regulatory role of these pluripotency factors in G1 dynamics in the context of stem cells and cancer cells, which may offer new insights into the interconnections between pluripotency and tumorigenesis.
Collapse
Affiliation(s)
| | - Jeanette Gowen Cook
- Department of Biochemistry & Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
| |
Collapse
|
|
9
|
Fu X, Zhuang Q, Babarinde IA, Shi L, Ma G, Hu H, Li Y, Chen J, Xiao Z, Deng B, Sun L, Jauch R, Hutchins AP. Restricting epigenetic activity promotes the reprogramming of transformed cells to pluripotency in a line-specific manner. Cell Death Discov 2023; 9:245. [PMID: 37452056 PMCID: PMC10349098 DOI: 10.1038/s41420-023-01533-8] [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: 01/19/2023] [Revised: 06/15/2023] [Accepted: 06/28/2023] [Indexed: 07/18/2023] Open
Abstract
Somatic cell reprogramming and oncogenic transformation share surprisingly similar features, yet transformed cells are resistant to reprogramming. Epigenetic barriers must block transformed cells from reprogramming, but the nature of those barriers is unclear. In this study, we generated a systematic panel of transformed mouse embryonic fibroblasts (MEFs) using oncogenic transgenes and discovered transformed cell lines compatible with reprogramming when transfected with Oct4/Sox2/Klf4/Myc. By comparing the reprogramming-capable and incapable transformed lines we identified multiple stages of failure in the reprogramming process. Some transformed lines failed at an early stage, whilst other lines seemed to progress through a conventional reprogramming process. Finally, we show that MEK inhibition overcomes one critical reprogramming barrier by indirectly suppressing a hyperacetylated active epigenetic state. This study reveals that diverse epigenetic barriers underly resistance to reprogramming of transformed cells.
Collapse
Affiliation(s)
- Xiuling Fu
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Qiang Zhuang
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Isaac A Babarinde
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Liyang Shi
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Gang Ma
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Haoqing Hu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Yuhao Li
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Jiao Chen
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Zhen Xiao
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Boping Deng
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Li Sun
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Ralf Jauch
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Centre for Translational Stem Cell Biology, Hong Kong SAR, China
| | - Andrew P Hutchins
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
| |
Collapse
|
|
10
|
Okano LM, Fonseca LMMD, Erthal ID, Malta TM. Epigenomic integrative analysis pinpoint master regulator transcription factors associated with tumorigenesis in squamous cell carcinoma of oral tongue. Genet Mol Biol 2023; 46:e20220358. [PMID: 37338302 DOI: 10.1590/1678-4685-gmb-2022-0358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 05/04/2023] [Indexed: 06/21/2023] Open
Abstract
Head and Neck Cancer (HNC) is a heterogeneous group of cancers, which includes cancers arising in the oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. Epidemiological studies have revealed that several factors such as tobacco and alcohol use, exposure to environmental pollutants, viral infection, and genetic factors are risk factors for developing HNC. The squamous cell carcinoma of oral tongue (SCCOT), which is significantly more aggressive than the other forms of oral squamous cell carcinoma, presents a propensity for rapid local invasion and spread, and a high recurrence rate. Dysregulation in the epigenetic machinery of cancer cells might help uncover the mechanisms of SCOOT tumorigenesis. Here, we used DNA methylation changes to identify cancer-specific enhancers that were enriched for specific transcription factor binding sites (TFBS), and potential master regulator transcription factors (MRTF) associated with SCCOT. We identified the activation of MRTFs associated with increased invasiveness, metastasis, epithelial-to-mesenchymal transition, poor prognosis, and stemness. On the other hand, we found the downregulation of MRTFs associated with tumor suppression. The identified MRTFs should be further investigated to clarify their role in oral cancer tumorigenesis and for their potential use as biological markers.
Collapse
Affiliation(s)
- Larissa Miyuki Okano
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP, Brazil
| | | | - Isabela Dias Erthal
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto, SP, Brazil
| | - Tathiane Maistro Malta
- Universidade de São Paulo, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Ribeirão Preto, SP, Brazil
| |
Collapse
|
|
11
|
Martins-Neves SR, Sampaio-Ribeiro G, Gomes CMF. Self-Renewal and Pluripotency in Osteosarcoma Stem Cells' Chemoresistance: Notch, Hedgehog, and Wnt/β-Catenin Interplay with Embryonic Markers. Int J Mol Sci 2023; 24:8401. [PMID: 37176108 PMCID: PMC10179672 DOI: 10.3390/ijms24098401] [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: 03/31/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Osteosarcoma is a highly malignant bone tumor derived from mesenchymal cells that contains self-renewing cancer stem cells (CSCs), which are responsible for tumor progression and chemotherapy resistance. Understanding the signaling pathways that regulate CSC self-renewal and survival is crucial for developing effective therapies. The Notch, Hedgehog, and Wnt/β-Catenin developmental pathways, which are essential for self-renewal and differentiation of normal stem cells, have been identified as important regulators of osteosarcoma CSCs and also in the resistance to anticancer therapies. Targeting these pathways and their interactions with embryonic markers and the tumor microenvironment may be a promising therapeutic strategy to overcome chemoresistance and improve the prognosis for osteosarcoma patients. This review focuses on the role of Notch, Hedgehog, and Wnt/β-Catenin signaling in regulating CSC self-renewal, pluripotency, and chemoresistance, and their potential as targets for anti-cancer therapies. We also discuss the relevance of embryonic markers, including SOX-2, Oct-4, NANOG, and KLF4, in osteosarcoma CSCs and their association with the aforementioned signaling pathways in overcoming drug resistance.
Collapse
Affiliation(s)
- Sara R. Martins-Neves
- iCBR—Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (S.R.M.-N.)
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Gabriela Sampaio-Ribeiro
- iCBR—Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (S.R.M.-N.)
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal
- CACC—Clinical Academic Center of Coimbra, 3000-075 Coimbra, Portugal
| | - Célia M. F. Gomes
- iCBR—Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (S.R.M.-N.)
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal
- CACC—Clinical Academic Center of Coimbra, 3000-075 Coimbra, Portugal
| |
Collapse
|
|
12
|
Hyytiäinen A, Mroueh R, Peltonen J, Wennerstrand P, Mäkitie A, Al-Samadi A, Ventelä S, Salo T. Prognostic histological markers in oral tongue squamous cell carcinoma patients treated with (chemo)radiotherapy. APMIS 2023; 131:142-151. [PMID: 36695633 DOI: 10.1111/apm.13298] [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: 10/17/2022] [Accepted: 01/19/2023] [Indexed: 01/26/2023]
Abstract
Treatment of oral tongue squamous cell carcinoma (OTSCC) frequently includes surgery with postoperative radiotherapy (RT) or chemoradiotherapy (CRT). Resistance to RT or CRT remains a major clinical challenge and highlights the need to identify predictive markers for it. We included 71 OTSCC patients treated with surgery combined with RT or CRT. We evaluated the association between tumor budding, tumor-stroma ratio (TSR), depth of invasion (DOI), tumor-infiltrating lymphocytes (TILs), hypoxia-inducible factor-1alpha (HIF-1alpha) expression, octamer-binding transcription factor 4 (OCT4) expression, high-endothelial venules (HEVs), and disease-free survival (DFS) using uni- and multivariate analyses. No significant association was observed between the different histological and molecular markers (TSR, DOI, TILs, HEV, HIF-1alph, OCT4) and DFS. However, an associative trend between DOI, budding, and DFS was noted. Further studies with larger cohorts are needed to explore the prognostic value of DOI and budding for OTSCC patients treated with postoperative RT or CRT.
Collapse
Affiliation(s)
- Aini Hyytiäinen
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Rayan Mroueh
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.,Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer and Research, Helsinki, Finland
| | - Johanna Peltonen
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Pia Wennerstrand
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Antti Mäkitie
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.,Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden
| | - Ahmed Al-Samadi
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Sami Ventelä
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.,Department for Otorhinolaryngology, Head and Neck Surgery, University of Turku and Turku University Hospital, Turku, Finland.,FICAN West Cancer Centre, Turku, Finland
| | - Tuula Salo
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.,Medical Research Center, Oulu University Hospital, Oulu, Finland.,Department of Pathology, Helsinki University Hospital (HUS), Helsinki, Finland
| |
Collapse
|
|
13
|
Identity matters: cancer stem cells and tumour plasticity in head and neck squamous cell carcinoma. Expert Rev Mol Med 2023; 25:e8. [PMID: 36740973 DOI: 10.1017/erm.2023.4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Head and neck squamous cell carcinoma (HNSCC) represents frequent yet aggressive tumours that encompass complex ecosystems of stromal and neoplastic components including a dynamic population of cancer stem cells (CSCs). Recently, research in the field of CSCs has gained increased momentum owing in part to their role in tumourigenicity, metastasis, therapy resistance and relapse. We provide herein a comprehensive assessment of the latest progress in comprehending CSC plasticity, including newly discovered influencing factors and their possible application in HNSCC. We further discuss the dynamic interplay of CSCs within tumour microenvironment considering our evolving appreciation of the contribution of oral microbiota and the pressing need for relevant models depicting their features. In sum, CSCs and tumour plasticity represent an exciting and expanding battleground with great implications for cancer therapy that are only beginning to be appreciated in head and neck oncology.
Collapse
|
|
14
|
Siqueira JM, Heguedusch D, Rodini CO, Nunes FD, Rodrigues MFSD. Mechanisms involved in cancer stem cell resistance in head and neck squamous cell carcinoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:116-137. [PMID: 37065869 PMCID: PMC10099599 DOI: 10.20517/cdr.2022.107] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/04/2023] [Accepted: 02/08/2023] [Indexed: 04/18/2023]
Abstract
Despite scientific advances in the Oncology field, cancer remains a leading cause of death worldwide. Molecular and cellular heterogeneity of head and neck squamous cell carcinoma (HNSCC) is a significant contributor to the unpredictability of the clinical response and failure in cancer treatment. Cancer stem cells (CSCs) are recognized as a subpopulation of tumor cells that can drive and maintain tumorigenesis and metastasis, leading to poor prognosis in different types of cancer. CSCs exhibit a high level of plasticity, quickly adapting to the tumor microenvironment changes, and are intrinsically resistant to current chemo and radiotherapies. The mechanisms of CSC-mediated therapy resistance are not fully understood. However, they include different strategies used by CSCs to overcome challenges imposed by treatment, such as activation of DNA repair system, anti-apoptotic mechanisms, acquisition of quiescent state and Epithelial-mesenchymal transition, increased drug efflux capacity, hypoxic environment, protection by the CSC niche, overexpression of stemness related genes, and immune surveillance. Complete elimination of CSCs seems to be the main target for achieving tumor control and improving overall survival for cancer patients. This review will focus on the multi-factorial mechanisms by which CSCs are resistant to radiotherapy and chemotherapy in HNSCC, supporting the use of possible strategies to overcome therapy failure.
Collapse
Affiliation(s)
- Juliana Mota Siqueira
- Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Daniele Heguedusch
- Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Camila Oliveira Rodini
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo 17012-230, Brazil
| | - Fabio Daumas Nunes
- Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo 05508-000, Brazil
| | - Maria Fernanda Setúbal Destro Rodrigues
- Biophotonics Applied to Health Sciences, Nove de Julho University, UNINOVE, São Paulo 01504-001, Brazil
- Correspondence to: PhD. Maria Fernanda Setúbal Destro Rodrigues. Biophotonics Applied to Health Sciences, Nove de Julho University, UNINOVE, Rua Vergueiro, 235/249 - Liberdade, São Paulo 01504-001, Brazil. E-mail:
| |
Collapse
|
|
15
|
Resistance to tyrosine kinase inhibitors promotes renal cancer progression through MCPIP1 tumor-suppressor downregulation and c-Met activation. Cell Death Dis 2022; 13:814. [PMID: 36138026 PMCID: PMC9500022 DOI: 10.1038/s41419-022-05251-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 02/08/2023]
Abstract
Tyrosine kinase inhibitors (TKIs) are the most commonly used targeted therapeutics in clear-cell renal cell carcinoma (ccRCC); however, drug resistance limits their utility and can lead to tumor "flare-up" and progression. In this study, we show that RCC resistance to sunitinib and sorafenib involves different mechanisms and leads to increased malignancy. Sunitinib decreased tumor growth and cell motility along with increased E-cadherin expression and secretion of the proangiogenic cytokines IL6 and IL8, which activated senescence in ccRCC cells and led to VE-cadherin phosphorylation, enhancing tumor angiogenesis. Sorafenib resistance increased the levels of mesenchymal markers and the secretion of MMP9, which cleaved VE-cadherin and disrupted endothelial cell integrity. Both sunitinib resistance and sorafenib resistance led to activation of the c-Met receptor IRAK1 and downregulation of the tumor suppressor MCPIP1, resulting in an increase in the metastasis of resistant cells, possibly due in part to enhanced vascularization of ccRCC. MCPIP1 overexpression partially overcame resistance to these drugs by decreasing micrometastasis and decreasing the expression of factors involved in tumorigenesis. In tumor samples from ccRCC patients, we observed a significant increase in the level of the c-Met receptor, IRAK1 and a decrease in MCPIP1 with respect to normal kidney tissue. Our results indicate separate novel mechanisms for sunitinib and sorafenib resistance, which both lead to MCPIP1 inhibition and ccRCC progression. The presented study suggests caution in the treatment of RCC with TKIs, which may lead to the unintended outcome of tumor progression.
Collapse
|
|
16
|
OCT4-mediated transcription confers oncogenic advantage for a subset of gastric tumors with poor clinical outcome. Funct Integr Genomics 2022; 22:1345-1360. [DOI: 10.1007/s10142-022-00894-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 11/26/2022]
|
|
17
|
Xie W, Yu J, Yin Y, Zhang X, Zheng X, Wang X. OCT4 induces EMT and promotes ovarian cancer progression by regulating the PI3K/AKT/mTOR pathway. Front Oncol 2022; 12:876257. [PMID: 36033461 PMCID: PMC9399417 DOI: 10.3389/fonc.2022.876257] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022] Open
Abstract
Background Octamer-binding transcription factor 4 (OCT4) is a key stem cell transcription factor involved in the development of various cancers. The role of OCT4 in ovarian cancer (OC) progression and its molecular mechanism are not fully understood. Methods First, immunohistochemistry (IHC) assays of ovarian benign cyst tissues, OC tissues, and omental metastatic tissues were performed to reveal OCT4 expression profiles. We knocked down OCT4 in two OC cell lines (SKOV3 and A2780) using a lentiviral vector and performed in vitro and in vivo experiments. OCT4 was knocked down to assess the proliferation, migration, and invasion of OC cells using CCK-8, colony formation, wound healing, and Transwell assays. In addition, the nude tumor mouse model was used for in vivo study. Mechanistically, we demonstrated that OCT4 influenced protein expression in the phosphoinositol 3-kinase (PI3K)/AKT/mTOR pathway and epithelial-mesenchymal transition (EMT)-related proteins by Western blotting and immunofluorescence (IF) assays. The interaction between OCT4 and p-AKT was further confirmed by coimmunoprecipitation (CoIP) assays. Importantly, AKT activation by its activator SC79 reversed the biological functions of OCT4 knockdown. Results OCT4 expression was significantly upregulated in OC samples and metastatic tissues. OCT4 knockdown notably inhibited the proliferation, migration, and invasion of OC cells in vitro and in vivo. Moreover, the expression of p-PI3K, p-AKT, and p-mTOR was downregulated after OCT4 knockdown. An AKT agonist reversed the effect of OCT4 knockdown on OC cells. EMT in OC samples was enhanced by OCT4. Conclusions Our study shows that OCT4 promotes the proliferation, migration, and invasion of OC cells by participating in the PI3K/AKT/mTOR signaling axis, suggesting that it could serve as a potential therapeutic target for OC patients.
Collapse
|
|
18
|
Patel U, Kannan S, Rane SU, Mittal N, Gera P, Patil A, Manna S, Shejwal V, Noronha V, Joshi A, Patil VM, Prabhash K, Mahimkar MB. Prognostic and predictive roles of cancer stem cell markers in head and neck squamous cell carcinoma patients receiving chemoradiotherapy with or without nimotuzumab. Br J Cancer 2022; 126:1439-1449. [PMID: 35140342 PMCID: PMC9091234 DOI: 10.1038/s41416-022-01730-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/07/2022] [Accepted: 01/28/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are needed to identify the patients most likely to benefit from these therapies. Here, we present predictive and prognostic associations of different cancer stem cell markers in HPV-negative locally advanced (LA) HNSCC patients. METHODS Pretreatment tumour tissues of 404 HPV-negative LA-HNSCCs patients, a subset of-phase 3-randomised study comparing cisplatin-radiation(CRT) and nimotuzumab plus cisplatin-radiation(NCRT) were examined. The expression levels of CD44, CD44v6, CD98hc, ALDH1A1, SOX2 and OCT4A were evaluated using immunohistochemistry. Progression-free survival(PFS), loco-regional control(LRC),- and overall survival(OS) were estimated by Kaplan-Meier method. Hazard ratios were estimated by Cox proportional hazard models. RESULTS NCRT showed significantly improved OS with low membrane expression of CD44 compared to CRT [HR (95% CI) = 0.63 (0.46-0.88)]. Patients with low CD44v6 also showed better outcomes with NCRT [LRC: HR (95% CI) = 0.25 (0.10-0.62); OS: HR (95% CI) = 0.38 (0.19-0.74)]. No similar benefit with NCRT observed in patients with high CD44 or CD44v6 expression. Bootstrap resampling confirmed the predictive effect of CD44 (Interaction P = 0.015) and CD44v6 (Interaction P = 0.041) for OS. Multivariable Cox analysis revealed an independent negative prognostic role of CD98hc membrane expression for LRC [HR (95% CI) = 0.63(0.39-1.0)] and OS[HR (95% CI) = 0.62 (0.40-0.95)]. CONCLUSIONS CD44 and CD44v6 are potential predictive biomarkers for NCRT response. CD98hc emerged as an independent negative prognostic biomarker. CLINICAL TRIAL REGISTRATION Registered with the Clinical Trial Registry of India (Trial registration identifier-CTRI/2014/09/004980).
Collapse
Affiliation(s)
- Usha Patel
- grid.410871.b0000 0004 1769 5793Mahimkar Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India ,grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Sadhana Kannan
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Biostatistician, Clinical Research Secretariat, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Swapnil U. Rane
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Department of Pathology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Neha Mittal
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Poonam Gera
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Biorepository, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Asawari Patil
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Department of Pathology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Subhakankha Manna
- grid.410871.b0000 0004 1769 5793Mahimkar Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Vishwayani Shejwal
- grid.410871.b0000 0004 1769 5793Mahimkar Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Vanita Noronha
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Amit Joshi
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Vijay M. Patil
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Kumar Prabhash
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India ,grid.410871.b0000 0004 1769 5793Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Manoj B. Mahimkar
- grid.410871.b0000 0004 1769 5793Mahimkar Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India ,grid.450257.10000 0004 1775 9822Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| |
Collapse
|
|
19
|
Tang Y, Yang X, Wang Q, Huang H, Wang Q, Jiang M, Yuan C, Huang Y, Chen Y. ING4 Promotes Stemness Enrichment of Human Renal Cell Carcinoma Cells Through Inhibiting DUSP4 Expression to Activate the p38 MAPK/type I IFN-Stimulated Gene Signaling Pathway. Front Pharmacol 2022; 13:845097. [PMID: 35496267 PMCID: PMC9046557 DOI: 10.3389/fphar.2022.845097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/21/2022] [Indexed: 12/01/2022] Open
Abstract
Renal cell carcinoma (RCC) recurs frequently due to high metastatic spread, resulting in a high mortality. Cancer stem cells play a critical role in initiating the tumor metastasis. Inhibitor of growth 4 (ING4) is a member of the ING family, but its impact on cancer stem cells in RCC is still unknown. In this study, we found that ING4 significantly promoted the sphere-forming size and number of RCC cells under an ultralow-attachment culture condition in vitro, tumor growth and metastasis in vivo, and the expression of some stem-like or pluripotent biomarkers CD44, MYC, OCT4, and NANOG, indicating that ING4 increased the stemness enrichment of RCC cells. Mechanistically, the ING4-activated p38 MAPK pathway possibly upregulated the expression of type I IFN-stimulated genes to promote the formation of RCC stem cells. ING4 could inhibit the expression of DUSP4 to activate p38 MAPK. In addition, selective pharmacological p38 MAPK inhibitors could significantly inhibit stemness enrichment only in ING4-overexpressed RCC cells, suggesting that the p38 MAPK inhibitors might be effective in patients with high ING4 expression in RCC tissue. Taken together, our findings proposed that ING4 might serve as a potential therapeutic target for metastatic RCC, particularly RCC stem cells.
Collapse
Affiliation(s)
- Yu Tang
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
- Key Lab of Environment and Health, Xuzhou Medical University, Xuzhou, China
| | - Xinyue Yang
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
- Key Lab of Environment and Health, Xuzhou Medical University, Xuzhou, China
| | - Qing Wang
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
- Key Lab of Environment and Health, Xuzhou Medical University, Xuzhou, China
| | - Haoyu Huang
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
- Key Lab of Environment and Health, Xuzhou Medical University, Xuzhou, China
| | - Qinzhi Wang
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
- Key Lab of Environment and Health, Xuzhou Medical University, Xuzhou, China
| | - Min Jiang
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
- Key Lab of Environment and Health, Xuzhou Medical University, Xuzhou, China
| | - Chunluan Yuan
- Department of Oncology, First People’s Hospital of Lianyungang, Lianyungang, China
| | - Yefei Huang
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
- Key Lab of Environment and Health, Xuzhou Medical University, Xuzhou, China
| | - Yansu Chen
- Key Laboratory of Human Genetics and Environmental Medicine, School of Public Health, Xuzhou Medical University, Xuzhou, China
- Key Lab of Environment and Health, Xuzhou Medical University, Xuzhou, China
- *Correspondence: Yansu Chen,
| |
Collapse
|
|
20
|
Gaja SK, Bandi S, Pavuluri PK, Sambyal S, Jaina VK, Sampath Kumar HM, Andugulapati SB, V R, Babu KS. Synthesis and antiproliferative activities of novel piscidinol a derivatives as potential anticancer agents. Nat Prod Res 2022:1-7. [PMID: 35343322 DOI: 10.1080/14786419.2022.2056889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Piscidinol A (1), a major compound isolated from Aphanamixis polystachya, showed modest anticancer activity against cancer cell lines. Subsequently, a series of analogues were synthesised by modification of the key structural functionalities of this high yield natural product and assessed for their anticancer potential against various cancer cell lines. Among the tested derivatives, the compounds 6e and 6i are significantly reduced the cell viability at 5.38 and 5.02 µM against DU145 prostate cancer cells, respectively. Additionally, both the compounds arrested the cell cycle at S phase and induced the late apoptosis in DU145 cells. Together, the results demonstrated that the compounds 6e and 6i could be a promising lead for the development of anticancer agents against DU145 and well worth further investigation aiming to generate potential anticancer agents.
Collapse
Affiliation(s)
- Swarna Kumari Gaja
- Centre for Natural Products & Traditional Knowledge, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India
| | - Siva Bandi
- Centre for Natural Products & Traditional Knowledge, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India
| | - Pavan Kumar Pavuluri
- Centre for Natural Products & Traditional Knowledge, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India
| | - Shainy Sambyal
- Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India
| | - Vinod Kumar Jaina
- Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India
| | - H M Sampath Kumar
- Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India
| | - Sai Balaji Andugulapati
- Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Ramalingam V
- Centre for Natural Products & Traditional Knowledge, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - K Suresh Babu
- Centre for Natural Products & Traditional Knowledge, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| |
Collapse
|
|
21
|
Liu Y, Yang Y, Suo Y, Li C, Chen M, Zheng S, Li H, Tang C, Fan N, Lan T, Zhou J, Li Y, Wang J, Chen H, Zou Q, Lai L. Inducible caspase-9 suicide gene under control of endogenous oct4 to safeguard mouse and human pluripotent stem cell therapy. Mol Ther Methods Clin Dev 2022; 24:332-341. [PMID: 35229007 PMCID: PMC8851157 DOI: 10.1016/j.omtm.2022.01.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/26/2022] [Indexed: 12/22/2022]
Abstract
Pluripotent stem cells (PSCs) are promising in regenerative medicine. A major challenge of PSC therapy is the risk of teratoma formation because of the contamination of undifferentiated stem cells. Constitutive promoters or endogenous SOX2 promoters have been used to drive inducible caspase-9 (iCasp9) gene expression but cannot specifically eradicate undifferentiated PSCs. Here, we inserted iCasp9 gene into the endogenous OCT4 locus of human and mouse PSCs without affecting their pluripotency. A chemical inducer of dimerization (CID), AP1903, induced iCasp9 activation, which led to the apoptosis of specific undifferentiated PSCs in vitro and in vivo. Differentiated cell lineages survived because of the silence of the endogenous OCT4 gene. Human and mouse PSCs were controllable when CID was administrated within 2 weeks after PSC injection in immunodeficient mice. However, an interval longer than 2 weeks caused teratoma formation and mouse death because a mass of somatic cells already differentiated from the PSCs. In conclusion, we have developed a specific and efficient PSC suicide system that will be of value in the clinical applications of PSC-based therapy.
Collapse
Affiliation(s)
- Yang Liu
- School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.,Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China.,CAS Key Laboratory of Regenerative Biology, Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yang Yang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Yangyang Suo
- Joint School of Life Science, Guangzhou Institutes of Biomedicine and Health, Chinese Academic and Sciences, Guangzhou Medical University, Guangzhou 511495, China
| | - Chuan Li
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Min Chen
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Shuwen Zheng
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Hao Li
- CAS Key Laboratory of Regenerative Biology, Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Chengcheng Tang
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Nana Fan
- CAS Key Laboratory of Regenerative Biology, Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Ting Lan
- CAS Key Laboratory of Regenerative Biology, Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Jizeng Zhou
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Yingying Li
- CAS Key Laboratory of Regenerative Biology, Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Jiaowei Wang
- CAS Key Laboratory of Regenerative Biology, Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Huangyao Chen
- CAS Key Laboratory of Regenerative Biology, Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Qingjian Zou
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Liangxue Lai
- School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.,Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China.,CAS Key Laboratory of Regenerative Biology, Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Joint Research Laboratory on Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China.,Research Unit of Generation of Large Animal Disease Models, Chinese Academy of Medical Sciences (2019RU015), Guangzhou 510530, China
| |
Collapse
|
|
22
|
Routila J, Qiao X, Weltner J, Rantala JK, Carpén T, Hagström J, Mäkitie A, Leivo I, Ruuskanen M, Söderlund J, Rintala M, Hietanen S, Irjala H, Minn H, Westermarck J, Ventelä S. Cisplatin overcomes radiotherapy resistance in OCT4-expressing head and neck squamous cell carcinoma. Oral Oncol 2022; 127:105772. [PMID: 35245886 DOI: 10.1016/j.oraloncology.2022.105772] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Cisplatin is combined with radiotherapy for advanced head and neck squamous cell carcinoma (HNSCC). While providing a beneficial effect on survival, it also causes side effects and thus is an important target when considering treatment de-escalation. Currently, there are no biomarkers to predict its patient-selective therapeutic utility. In this study, we examined the role of the stem cell factor OCT4 as a potential biomarker to help clinicians stratify HNSCC patients between radiotherapy and chemoradiotherapy. MATERIALS AND METHODS OCT4 immunohistochemical staining of a population-validated tissue microarray (PV-TMA) (n = 166) representative of a standard HNSCC patients was carried out, and 5-year survival was analyzed. The results were validated using ex vivo drug sensitivity analysis of HNSCC tumor samples, and further cross-validated in independent oropharyngeal (n = 118), nasopharyngeal (n = 170), and vulvar carcinoma (n = 95) clinical datasets. In vitro, genetically modified, patient-derived HNSCC cells were used. RESULTS OCT4 expression in HNSCC tumors was associated with radioresistance. However, combination therapy with cisplatin was found to overcome thisradioresistance in OCT4-expressing HNSCC tumors. The results were validated by using several independent patient cohorts. Furthermore, CRISPRa-based OCT4 overexpression in the HNSCC cell line resulted in apoptosis resistance, and cisplatin was found to downregulate OCT4 protein expression in vitro. Ex vivo drug sensitivity analysis of HNSCC tumors confirmed the association between OCT4 expression and cisplatin sensitivity. CONCLUSION This study introduces OCT4 immunohistochemistry as a simple and cost-effective diagnostic approach for clinical practice to identify HNSCC patients benefitting from radiosensitization by cisplatin using either full or reduced dosing.
Collapse
Affiliation(s)
- Johannes Routila
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Xi Qiao
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Jere Weltner
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, SE-14186 Stockholm, Sweden and Division of Obstetrics and Gynecology, Karolinska Universitetssjukhuset, SE-14186 Stockholm, Sweden
| | - Juha K Rantala
- MISVIK Biology Ltd, Karjakatu 35 B, 20520 Turku, Finland
| | - Timo Carpén
- Department for Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, P.O.Box 263, FI-00029 HUS Helsinki, Finland
| | - Jaana Hagström
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Antti Mäkitie
- Department for Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, P.O.Box 263, FI-00029 HUS Helsinki, Finland
| | - Ilmo Leivo
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland; Institute of Biomedicine, Pathology, University of Turku, Kiinamyllynkatu 10 D, 20520 Turku, Finland
| | - Miia Ruuskanen
- Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Jenni Söderlund
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland
| | - Marjut Rintala
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland
| | - Sakari Hietanen
- Department of Obstetrics and Gynecology, Turku University Hospital and University of Turku, Turku, Finland; FICAN West Cancer Centre, Turku, Finland
| | - Heikki Irjala
- Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland
| | - Heikki Minn
- FICAN West Cancer Centre, Turku, Finland; Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, Turku, Finland
| | - Jukka Westermarck
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Biomedical Institute, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; FICAN West Cancer Centre, Turku, Finland
| | - Sami Ventelä
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland; Department for Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland; FICAN West Cancer Centre, Turku, Finland.
| |
Collapse
|
|
23
|
Xiao J, He X. Involvement of Non-Coding RNAs in Chemo- and Radioresistance of Nasopharyngeal Carcinoma. Cancer Manag Res 2021; 13:8781-8794. [PMID: 34849030 PMCID: PMC8627240 DOI: 10.2147/cmar.s336265] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/04/2021] [Indexed: 12/16/2022] Open
Abstract
The crucial treatment for nasopharyngeal carcinoma (NPC) is radiation therapy supplemented by chemotherapy. However, long-term radiation therapy can cause some genetic and proteomic changes to produce radiation resistance, leading to tumour recurrence and poor prognosis. Therefore, the search for new markers that can overcome the resistance of tumor cells to drugs and radiotherapy and improve the sensitivity of tumor cells to drugs and radiotherapy is one of the most important goals of pharmacogenomics and cancer research, which is important for predicting treatment response and prognosis. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), may play important roles in regulating chemo- and radiation resistance in nasopharyngeal carcinoma by controlling the cell cycle, proliferation, apoptosis, and DNA damage repair, as well as other signalling pathways. Recent research has suggested that selective modulation of ncRNA activity can improve the response to chemotherapy and radiotherapy, providing an innovative antitumour approach based on ncRNA-related gene therapy. Therefore, ncRNAs can serve as biomarkers for tumour prediction and prognosis, play a role in overcoming drug resistance and radiation resistance in NPC, and can also serve as targets for developing new therapeutic strategies. In this review, we discuss the involvement of ncRNAs in chemotherapy and radiation resistance in NPC. The effects of these molecules on predicting therapeutic cancer are highlighted.
Collapse
Affiliation(s)
- Jiaxin Xiao
- Hunan Province Key Laboratory of Tumour Cellular & Molecular Pathology Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang, 421001, Hunan Province, People’s Republic of China
| | - Xiusheng He
- Hunan Province Key Laboratory of Tumour Cellular & Molecular Pathology Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang, 421001, Hunan Province, People’s Republic of China
| |
Collapse
|
|
24
|
Singh P, Augustine D, Rao RS, Patil S, Awan KH, Sowmya SV, Haragannavar VC, Prasad K. Role of cancer stem cells in head-and-neck squamous cell carcinoma - A systematic review. J Carcinog 2021; 20:12. [PMID: 34729044 PMCID: PMC8511833 DOI: 10.4103/jcar.jcar_14_20] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/30/2020] [Accepted: 12/05/2020] [Indexed: 11/24/2022] Open
Abstract
Targeting cancer stem cell (CSC) subpopulation within the tumor remains an obstacle for specific therapy in head-and-neck squamous cell carcinoma (HNSCC). Few studies in the literature describe a panel of stem cell makers, however a distinct panel has not been put forth. This systematic review aims to enhance the knowledge of additional markers to accurately relate their expression to tumorigenesis, metastasis, and therapy resistance. Databases, including PubMed, Google Scholar, Ebsco, and Science Direct, were searched from 2010 to 2017 using various combinations of the following keywords: “Stem cell markers in HNSCC” and “chemoresistance and radioresistence in HNSCC.” Original experimental studies (both in vitro and in vivo) published in English considering stem cell markers in HNSCC, were considered and included. We excluded articles on tumors other than HNSCC, reviews, editorial letters, book chapters, opinions, and abstracts from the analyses. Forty-two articles were included, in which 13 types of stem cell markers were identified. The most commonly expressed CSC markers were CD44, aldehyde dehydrogenase, and CD133, which were responsible for tumorigenesis, self-renewal, and therapy resistance, whereas NANOG, SOX-2, and OCT-4 were involved in metastasis and invasion. Identification of an accurate panel of CSC markers is the need of the hour as nonspecificity of the current markers poses a problem. Further studies with a large sample size would help validate the role of these CSC markers in HNSCC. These CSC proteins can be developed as therapeutic targets for HNSCC therapy, making future treatment modality more specific and effective.
Collapse
Affiliation(s)
- Preeti Singh
- Departments of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
| | - Dominic Augustine
- Departments of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
| | - Roopa S Rao
- Departments of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | - Kamran Habib Awan
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah, USA
| | - Samudrala Venkatesiah Sowmya
- Departments of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
| | - Vanishri C Haragannavar
- Departments of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
| | - Kavitha Prasad
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
| |
Collapse
|
|
25
|
Pluripotency Stemness and Cancer: More Questions than Answers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1376:77-100. [PMID: 34725790 DOI: 10.1007/5584_2021_663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Embryonic stem cells and induced pluripotent stem cells provided us with fascinating new knowledge in recent years. Mechanistic insight into intricate regulatory circuitry governing pluripotency stemness and disclosing parallels between pluripotency stemness and cancer instigated numerous studies focusing on roles of pluripotency transcription factors, including Oct4, Sox2, Klf4, Nanog, Sall4 and Tfcp2L1, in cancer. Although generally well substantiated as tumour-promoting factors, oncogenic roles of pluripotency transcription factors and their clinical impacts are revealing themselves as increasingly complex. In certain tumours, both Oct4 and Sox2 behave as genuine oncogenes, and reporter genes driven by composite regulatory elements jointly recognized by both the factors can identify stem-like cells in a proportion of tumours. On the other hand, cancer stem cells seem to be biologically very heterogeneous both among different tumour types and among and even within individual tumours. Pluripotency transcription factors are certainly implicated in cancer stemness, but do not seem to encompass its entire spectrum. Certain cancer stem cells maintain their stemness by biological mechanisms completely different from pluripotency stemness, sometimes even by engaging signalling pathways that promote differentiation of pluripotent stem cells. Moreover, while these signalling pathways may well be antithetical to stemness in pluripotent stem cells, they may cooperate with pluripotency factors in cancer stem cells - a paradigmatic example is provided by the MAPK-AP-1 pathway. Unexpectedly, forced expression of pluripotency transcription factors in cancer cells frequently results in loss of their tumour-initiating ability, their phenotypic reversion and partial epigenetic normalization. Besides the very different signalling contexts operating in pluripotent and cancer stem cells, respectively, the pronounced dose dependency of reprogramming pluripotency factors may also contribute to the frequent loss of tumorigenicity observed in induced pluripotent cancer cells. Finally, contradictory cell-autonomous and non-cell-autonomous effects of various signalling molecules operate during pluripotency (cancer) reprogramming. The effects of pluripotency transcription factors in cancer are thus best explained within the concept of cancer stem cell heterogeneity.
Collapse
|
|
26
|
Herzog AE, Warner KA, Zhang Z, Bellile E, Bhagat MA, Castilho RM, Wolf GT, Polverini PJ, Pearson AT, Nör JE. The IL-6R and Bmi-1 axis controls self-renewal and chemoresistance of head and neck cancer stem cells. Cell Death Dis 2021; 12:988. [PMID: 34689150 PMCID: PMC8542035 DOI: 10.1038/s41419-021-04268-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/28/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022]
Abstract
Despite major progress in elucidating the pathobiology of head and neck squamous cell carcinoma (HNSCC), the high frequency of disease relapse correlates with unacceptably deficient patient survival. We previously showed that cancer stem-like cells (CSCs) drive tumorigenesis and progression of HNSCC. Although CSCs constitute only 2–5% of total tumor cells, CSCs contribute to tumor progression by virtue of their high tumorigenic potential and their resistance to chemo-, radio-, and immunotherapy. Not only are CSCs resistant to therapy, but cytotoxic agents actually enhance cancer stemness by activating transcription of pluripotency factors and by inducing expression of Bmi-1, a master regulator of stem cell self-renewal. We hypothesized therapeutic inhibition of interleukin-6 receptor (IL-6R) suppresses Bmi-1 to overcome intrinsic chemoresistance of CSCs. We observed that high Bmi-1 expression correlates with decreased (p = 0.04) recurrence-free survival time in HNSCC patients (n = 216). Blockade of IL-6R by lentiviral knockdown or pharmacologic inhibition with a humanized monoclonal antibody (Tocilizumab) is sufficient to inhibit Bmi-1 expression, secondary sphere formation, and to decrease the CSC fraction even in Cisplatin-resistant HNSCC cells. IL-6R inhibition with Tocilizumab abrogates Cisplatin-mediated increase in CSC fraction and induction of Bmi-1 in patient-derived xenograft (PDX) models of HNSCC. Notably, Tocilizumab inhibits Bmi-1 and suppresses growth of xenograft tumors generated with Cisplatin-resistant HNSCC cells. Altogether, these studies demonstrate that therapeutic blockade of IL-6R suppresses Bmi-1 function and inhibits cancer stemness. These results suggest therapeutic inhibition of IL-6R might be a viable strategy to overcome the CSC-mediated chemoresistance typically observed in HNSCC patients.
Collapse
Affiliation(s)
- Alexandra E Herzog
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Kristy A Warner
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Zhaocheng Zhang
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Emily Bellile
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Meera A Bhagat
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Rogerio M Castilho
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Gregory T Wolf
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Peter J Polverini
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.,Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA
| | - Alexander T Pearson
- Department of Hematology/Oncology, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA. .,University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
| | - Jacques E Nör
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA. .,Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. .,Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA. .,University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
| |
Collapse
|
|
27
|
Tayler IM, Stowers RS. Engineering hydrogels for personalized disease modeling and regenerative medicine. Acta Biomater 2021; 132:4-22. [PMID: 33882354 DOI: 10.1016/j.actbio.2021.04.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/26/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023]
Abstract
Technological innovations and advances in scientific understanding have created an environment where data can be collected, analyzed, and interpreted at scale, ushering in the era of personalized medicine. The ability to isolate cells from individual patients offers tremendous promise if those cells can be used to generate functional tissue replacements or used in disease modeling to determine optimal treatment strategies. Here, we review recent progress in the use of hydrogels to create artificial cellular microenvironments for personalized tissue engineering and regenerative medicine applications, as well as to develop personalized disease models. We highlight engineering strategies to control stem cell fate through hydrogel design, and the use of hydrogels in combination with organoids, advanced imaging methods, and novel bioprinting techniques to generate functional tissues. We also discuss the use of hydrogels to study molecular mechanisms underlying diseases and to create personalized in vitro disease models to complement existing pre-clinical models. Continued progress in the development of engineered hydrogels, in combination with other emerging technologies, will be essential to realize the immense potential of personalized medicine. STATEMENT OF SIGNIFICANCE: In this review, we cover recent advances in hydrogel engineering strategies with applications in personalized medicine. Specifically, we focus on material systems to expand or control differentiation of patient-derived stem cells, and hydrogels to reprogram somatic cells to pluripotent states. We then review applications of hydrogels in developing personalized engineered tissues. We also highlight the use of hydrogel systems as personalized disease models, focusing on specific examples in fibrosis and cancer, and more broadly on drug screening strategies using patient-derived cells and hydrogels. We believe this review will be a valuable contribution to the Special Issue and the readership of Acta Biomaterialia will appreciate the comprehensive overview of the utility of hydrogels in the developing field of personalized medicine.
Collapse
|
|
28
|
Cancer Stem Cells in Oropharyngeal Cancer. Cancers (Basel) 2021; 13:cancers13153878. [PMID: 34359786 PMCID: PMC8345685 DOI: 10.3390/cancers13153878] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/17/2021] [Accepted: 07/20/2021] [Indexed: 12/16/2022] Open
Abstract
Oropharyngeal cancer (OPC), which is a common type of head and neck squamous cell carcinoma (HNSCC), is associated with tobacco and alcohol use, and human papillomavirus (HPV) infection. Underlying mechanisms and as a result prognosis of the HPV-positive and HPV-negative OPC patients are different. Like stem cells, the ability of self-renewal and differentiate, cancer stem cells (CSCs) have roles in tumor invasion, metastasis, drug resistance, and recurrence after therapy. Research revealed their roles to some extent in all of these processes but there are still many unresolved points to connect to CSC-targeted therapy. In this review, we will focus on what we currently know about CSCs of OPC and limitations of our current knowledge. We will present perspectives that will broaden our understanding and recent literature which may connect to therapy.
Collapse
|
|
29
|
Buart S, Terry S, Diop MK, Dessen P, Couvé S, Abdou A, Adam J, Thiery J, Savagner P, Chouaib S. The Most Common VHL Point Mutation R167Q in Hereditary VHL Disease Interferes with Cell Plasticity Regulation. Cancers (Basel) 2021; 13:3897. [PMID: 34359798 PMCID: PMC8345752 DOI: 10.3390/cancers13153897] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 01/16/2023] Open
Abstract
Von Hippel-Lindau disease (VHL) is a rare hereditary syndrome due to mutations of the VHL tumor suppressor gene. Patients harboring the R167Q mutation of the VHL gene have a high risk of developing ccRCCs. We asked whether the R167Q mutation with critical aspects of pseudo-hypoxia interferes with tumor plasticity. For this purpose, we used wild-type VHL (WT-VHL) and VHL-R167Q reconstituted cells. We showed that WT-VHL and VHL-R167Q expression had a similar effect on cell morphology and colony formation. However, cells transfected with VHL-R167Q display an intermediate, HIF2-dependent, epithelial-mesenchymal phenotype. Using RNA sequencing, we showed that this mutation upregulates the expression of genes involved in the hypoxia pathway, indicating that such mutation is conferring an enhanced pseudo-hypoxic state. Importantly, this hypoxic state correlates with the induction of genes belonging to epithelial-mesenchymal transition (EMT) and stemness pathways, as revealed by GSEA TCGA analysis. Moreover, among these deregulated genes, we identified nine genes specifically associated with a poor patient survival in the TCGA KIRC dataset. Together, these observations support the hypothesis that a discrete VHL point mutation interferes with tumor plasticity and may impact cell behavior by exacerbating phenotypic switching. A better understanding of the role of this mutation might guide the search for more effective treatments to combat ccRCCs.
Collapse
Affiliation(s)
- Stéphanie Buart
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France; (S.B.); (S.T.); (A.A.); (J.A.); (J.T.); (P.S.)
| | - Stéphane Terry
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France; (S.B.); (S.T.); (A.A.); (J.A.); (J.T.); (P.S.)
| | - M’boyba Khadija Diop
- Bioinformatics Core Facility, University of Paris-Saclay, 94805 Villejuif, France; (M.K.D.); (P.D.)
| | - Philippe Dessen
- Bioinformatics Core Facility, University of Paris-Saclay, 94805 Villejuif, France; (M.K.D.); (P.D.)
| | - Sophie Couvé
- EPHE, PSL Université, 75006 Paris, France;
- CNRS UMR 9019, Gustave Roussy, University Paris-Saclay, 94805 Villejuif, France
| | - Abdérémane Abdou
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France; (S.B.); (S.T.); (A.A.); (J.A.); (J.T.); (P.S.)
| | - Julien Adam
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France; (S.B.); (S.T.); (A.A.); (J.A.); (J.T.); (P.S.)
- Biology and Pathology Department, University Paris-Saclay, 94805 Villejuif, France
| | - Jérôme Thiery
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France; (S.B.); (S.T.); (A.A.); (J.A.); (J.T.); (P.S.)
| | - Pierre Savagner
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France; (S.B.); (S.T.); (A.A.); (J.A.); (J.T.); (P.S.)
| | - Salem Chouaib
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France; (S.B.); (S.T.); (A.A.); (J.A.); (J.T.); (P.S.)
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
| |
Collapse
|
|
30
|
Routila J, Suvila K, Grénman R, Leivo I, Westermarck J, Ventelä S. Cancer cell line microarray as a novel screening method for identification of radioresistance biomarkers in head and neck squamous cell carcinoma. BMC Cancer 2021; 21:868. [PMID: 34320941 PMCID: PMC8320194 DOI: 10.1186/s12885-021-08618-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 07/15/2021] [Indexed: 11/23/2022] Open
Abstract
Background Currently, no clinically useful biomarkers for radioresistance are available in head and neck squamous cell carcinoma (HNSCC). This study assesses the usefulness of Cell Line Microarray (CMA) method to enhance immunohistochemical screening of potential immunohistochemical biomarkers for radioresistance in HNSCC cell lines. Methods Twenty-nine HNSCC cell lines were cultured, cell pellets formalin-fixed, paraffin-embedded, and arrayed. Radioresistance features of the cell lines were combined to immunohistochemical stains for p53, NDFIP1, EGFR, stem cell marker Oct4, and PP2A inhibitor CIP2A. Results Expression of p53, EGFR or CIP2A did not indicate intrinsic radioresistance in vitro. Stem cell marker Oct4 nuclear positivity and NDFIP1 nuclear positivity was correlated with increased intrinsic radioresistance. Conclusion The usefulness of CMA in analysis of HNSCC cell lines and discovery of biomarkers is demonstrated. CMA is very well adapted to both testing of antibodies in a large panel of cell lines as well as correlating staining results with other cell line characteristics. In addition, CMA-based antibody screening proved an efficient and relatively simple method to identify potential radioresistance biomarkers in HNSCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08618-6.
Collapse
Affiliation(s)
- Johannes Routila
- Turku Bioscience Centre, University of Turku and Åbo Akademi university, Turku, Finland.,Department for Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, 20521, Turku, Finland.,Department for Otorhinolaryngology, Satakunta Central Hospital, Pori, Finland
| | - Karri Suvila
- Turku Bioscience Centre, University of Turku and Åbo Akademi university, Turku, Finland
| | - Reidar Grénman
- Department for Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, 20521, Turku, Finland
| | - Ilmo Leivo
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland
| | - Jukka Westermarck
- Turku Bioscience Centre, University of Turku and Åbo Akademi university, Turku, Finland.,Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland
| | - Sami Ventelä
- Turku Bioscience Centre, University of Turku and Åbo Akademi university, Turku, Finland. .,Department for Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, 20521, Turku, Finland. .,Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland.
| |
Collapse
|
|
31
|
Thankamony AP, Subbalakshmi AR, Jolly MK, Nair R. Lineage Plasticity in Cancer: The Tale of a Skin-Walker. Cancers (Basel) 2021; 13:3602. [PMID: 34298815 PMCID: PMC8306016 DOI: 10.3390/cancers13143602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/04/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022] Open
Abstract
Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here, we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of epithelial-mesenchymal transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.
Collapse
Affiliation(s)
- Archana P. Thankamony
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India;
- Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Ayalur Raghu Subbalakshmi
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Radhika Nair
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India;
| |
Collapse
|
|
32
|
Oct4 confers stemness and radioresistance to head and neck squamous cell carcinoma by regulating the homologous recombination factors PSMC3IP and RAD54L. Oncogene 2021; 40:4214-4228. [PMID: 34079088 PMCID: PMC8211562 DOI: 10.1038/s41388-021-01842-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 04/29/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is often being diagnosed at an advanced stage, conferring a poor prognosis. The probability of local tumor control after radiotherapy depends on the eradication of cancer stem cells (CSCs) with activated DNA repair. This study provides evidence that the CSC-related transcription factor Oct4 contributes to HNSCC radioresistance by regulating DNA damage response and the CSC phenotype. Knockdown of Oct4 A isoform reduced self-renewal capacity in HNSCC and led to partial tumor cell radiosensitization caused by transcriptional downregulation of the cell cycle checkpoint kinases CHK1 and WEE1 and homologous recombination (HR) repair genes PSMC3IP and RAD54L. Besides, PARP inhibition with Olaparib selectively radiosensitized Oct4 A knockout, but not wild-type HNSCC cells. This finding links Oct4 A to the HR-mediated DNA repair mechanisms. In turn, knockdown of PSMC3IP and RAD54L reduced the HNSCC self-renewal capacity and clonogenic cell survival after irradiation, suggesting the interplay between DNA repair and the CSC phenotype. Similar to the effect of Oct4 knockdown, overexpression of Oct4 also resulted in significant HNSCC radiosensitization and increased DNA damage, suggesting that Oct4-dependent regulation of DNA repair depends on its fine-tuned expression. In line with this observation, HNSCC patients with high and low nuclear Oct4 expression at the invasive tumor front exhibited better loco-regional tumor control after postoperative radio(chemo)therapy compared to the intermediate expression subgroup. Thus, we found that the Oct4-driven transcriptional program plays a critical role in regulating HNSCC radioresistance, and a combination of radiotherapy with PARP inhibitors may induce synthetic lethality in Oct4-deregulated tumors.
Collapse
|
|
33
|
Kim JW, Chung JY, Ylaya K, Park Y, Jun SY, Hong SM, Hewitt SM. Prognostic implication of SOX2 expression in small intestinal adenocarcinoma. Virchows Arch 2021; 478:1049-1060. [PMID: 33103210 PMCID: PMC9815101 DOI: 10.1007/s00428-020-02946-x] [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: 06/08/2020] [Revised: 09/23/2020] [Accepted: 10/05/2020] [Indexed: 01/11/2023]
Abstract
The presence of KRAS mutation enhances the stem cell features of colorectal carcinoma cells containing mutant adenomatous polyposis coli (APC). However, their potential role in small intestinal adenocarcinoma remains elusive. Here, we aimed to investigate the clinical significance of cancer stem cell markers expression in the context of small intestinal adenocarcinoma with the KRAS genotype. SOX2, NANOG, and OCT4 expression were assessed by immunohistochemistry and digital image analysis, and their potential association with KRAS was further examined in 185 Korean patients with small intestinal adenocarcinomas, which were collected from 22 institutions in South Korea. Positive expression of SOX2, NANOG, and OCT4 was detected in 65 (35.1%), 94 (50.8%), and 82 (44.3%) of patients, respectively. Patients with high SOX2 (SOX2+) expression displayed worse overall survival compared to those with low SOX2 (SOX2-) expression (P < 0.001). Patients with SOX2+/mutant KRAS (KRASMT) (11.1 months) had significantly shorter overall survival than those with SOX2-/KRASWT (53.6 months) (P < 0.001). In multivariate analysis, SOX2+, distal location, high pT and pN categories, microsatellite stable, and absence of predisposing diseases were independent prognostic factors for worse overall survival. These results suggest that SOX2 expression has the potential to predict clinical outcomes in patients with small intestinal adenocarcinomas.
Collapse
Affiliation(s)
- Jeong Won Kim
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA,Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Republic of Korea
| | - Joon-Yong Chung
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kris Ylaya
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yoonho Park
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sun-Young Jun
- Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 21431, Republic of Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05550, Republic of Korea
| | - Stephen M. Hewitt
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| |
Collapse
|
|
34
|
Zhou HM, Zhang JG, Zhang X, Li Q. Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents. Signal Transduct Target Ther 2021; 6:62. [PMID: 33589595 PMCID: PMC7884707 DOI: 10.1038/s41392-020-00430-1] [Citation(s) in RCA: 245] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/26/2020] [Accepted: 10/08/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) show a self-renewal capacity and differentiation potential that contribute to tumor progression and therapy resistance. However, the underlying processes are still unclear. Elucidation of the key hallmarks and resistance mechanisms of CSCs may help improve patient outcomes and reduce relapse by altering therapeutic regimens. Here, we reviewed the identification of CSCs, the intrinsic and extrinsic mechanisms of therapy resistance in CSCs, the signaling pathways of CSCs that mediate treatment failure, and potential CSC-targeting agents in various tumors from the clinical perspective. Targeting the mechanisms and pathways described here might contribute to further drug discovery and therapy.
Collapse
Affiliation(s)
- He-Ming Zhou
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Ji-Gang Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Xue Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Qin Li
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China.
| |
Collapse
|
|
35
|
Garikipati VNS, Arakelyan A, Blakely EA, Chang PY, Truongcao MM, Cimini M, Malaredy V, Bajpai A, Addya S, Bisserier M, Brojakowska A, Eskandari A, Khlgatian MK, Hadri L, Fish KM, Kishore R, Goukassian DA. Long-Term Effects of Very Low Dose Particle Radiation on Gene Expression in the Heart: Degenerative Disease Risks. Cells 2021; 10:387. [PMID: 33668521 PMCID: PMC7917872 DOI: 10.3390/cells10020387] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/27/2021] [Accepted: 02/08/2021] [Indexed: 12/13/2022] Open
Abstract
Compared to low doses of gamma irradiation (γ-IR), high-charge-and-energy (HZE) particle IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type and dose dependent. Three- to four-month-old female CB6F1/Hsd mice were exposed once to one of four different doses of the following types of radiation: γ-IR 137Cs (40-160 cGy, 0.662 MeV), 14Si-IR (4-32 cGy, 260 MeV/n), or 22Ti-IR (3-26 cGy, 1 GeV/n). At 16 months post-exposure, animals were sacrificed and hearts were harvested and archived as part of the NASA Space Radiation Tissue Sharing Forum. These heart tissue samples were used in our study for RNA isolation and microarray hybridization. Functional annotation of twofold up/down differentially expressed genes (DEGs) and bioinformatics analyses revealed the following: (i) there were no clear lower IR thresholds for HZE- or γ-IR; (ii) there were 12 common DEGs across all 3 IR types; (iii) these 12 overlapping genes predicted various degrees of cardiovascular, pulmonary, and metabolic diseases, cancer, and aging; and (iv) these 12 genes revealed an exclusive non-linear DEG pattern in 14Si- and 22Ti-IR-exposed hearts, whereas two-thirds of γ-IR-exposed hearts revealed a linear pattern of DEGs. Thus, our study may provide experimental evidence of excess relative risk (ERR) quantification of low/very low doses of full-body space-type IR-associated degenerative disease development.
Collapse
Affiliation(s)
- Venkata Naga Srikanth Garikipati
- Department of Emergency Medicine, Dorothy M Davis Heart and Lung Research Institute, Wexner Medical School, The Ohio State University, Columbus, OH 43210, USA;
| | - Arsen Arakelyan
- Bioinformatics Group, The Institute of Molecular Biology, The National Academy of Sciences of the Republic of Armenia, Yerevan 0014, Armenia;
- PathVerse, Yerevan 0014, Armenia
| | | | | | - May M. Truongcao
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (M.M.T.); (M.C.); (V.M.); (A.B.); (R.K.)
| | - Maria Cimini
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (M.M.T.); (M.C.); (V.M.); (A.B.); (R.K.)
| | - Vandana Malaredy
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (M.M.T.); (M.C.); (V.M.); (A.B.); (R.K.)
| | - Anamika Bajpai
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (M.M.T.); (M.C.); (V.M.); (A.B.); (R.K.)
| | - Sankar Addya
- Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Malik Bisserier
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (M.B.); (A.B.); (A.E.); (M.K.K.); (L.H.); (K.M.F.)
| | - Agnieszka Brojakowska
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (M.B.); (A.B.); (A.E.); (M.K.K.); (L.H.); (K.M.F.)
| | - Abrisham Eskandari
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (M.B.); (A.B.); (A.E.); (M.K.K.); (L.H.); (K.M.F.)
| | - Mary K. Khlgatian
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (M.B.); (A.B.); (A.E.); (M.K.K.); (L.H.); (K.M.F.)
| | - Lahouaria Hadri
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (M.B.); (A.B.); (A.E.); (M.K.K.); (L.H.); (K.M.F.)
| | - Kenneth M. Fish
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (M.B.); (A.B.); (A.E.); (M.K.K.); (L.H.); (K.M.F.)
| | - Raj Kishore
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (M.M.T.); (M.C.); (V.M.); (A.B.); (R.K.)
| | - David. A. Goukassian
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (M.B.); (A.B.); (A.E.); (M.K.K.); (L.H.); (K.M.F.)
| |
Collapse
|
|
36
|
Hsa-miR-3658 down-regulates OCT4 gene expression followed by suppressing SW480 cell proliferation and migration. Biochem J 2020; 477:2281-2293. [PMID: 32478824 DOI: 10.1042/bcj20190619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 05/20/2020] [Accepted: 06/01/2020] [Indexed: 01/04/2023]
Abstract
The pluripotency factor, OCT4 gene is a stemness marker that is involved in the tumorigenicity of different cancer types and knowing about molecular mechanisms of its regulation is crucially important. To date, a few microRNAs (miRNAs) are known to be regulators of OCT4 gene expression. Looking for the novel miRNAs which are capable of regulating OCT4 gene expression, our bioinformatics analysis introduced hsa-miR-3658 (miR-3658) as a bona fide candidate. Then, RT-qPCR results indicated that miR-3658 expression is decreased in colorectal cancer (CRC) tumor tissues, compared with normal pairs. Furthermore, RT-qPCR and western blot analysis showed that the OCT4 gene has been down-regulated following the miR-3658 overexpression. Consistently, dual-luciferase assay supported the direct interaction of miR-3658 with the 3'-UTR sequence of OCT4 gene. Unlike in HCT116 cells, overexpression of miR-3658 in SW480 cells brought about growth inhibition, cell cycle arrest and reduced cell migration, detected by flow cytometry, and scratch test assay. Overall, these findings demonstrated that miR-3658 as a tumor suppressor miRNA exerts its effect against OCT4 gene expression, and it has the potential of being used as a prognostic marker and therapeutic target against colorectal cancer.
Collapse
|
|
37
|
Scarola M, Comisso E, Rosso M, Del Sal G, Schneider C, Schoeftner S, Benetti R. FUS-dependent loading of SUV39H1 to OCT4 pseudogene-lncRNA programs a silencing complex with OCT4 promoter specificity. Commun Biol 2020; 3:632. [PMID: 33128015 PMCID: PMC7603346 DOI: 10.1038/s42003-020-01355-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 10/01/2020] [Indexed: 11/16/2022] Open
Abstract
The resurrection of pseudogenes during evolution produced lncRNAs with new biological function. Here we show that pseudogene-evolution created an Oct4 pseudogene lncRNA that is able to direct epigenetic silencing of the parental Oct4 gene via a 2-step, lncRNA dependent mechanism. The murine Oct4 pseudogene 4 (mOct4P4) lncRNA recruits the RNA binding protein FUS to allow the binding of the SUV39H1 HMTase to a defined mOct4P4 lncRNA sequence element. The mOct4P4-FUS-SUV39H1 silencing complex holds target site specificity for the parental Oct4 promoter and interference with individual components results in loss of Oct4 silencing. SUV39H1 and FUS do not bind parental Oct4 mRNA, confirming the acquisition of a new biological function by the mOct4P4 lncRNA. Importantly, all features of mOct4P4 function are recapitulated by the human hOCT4P3 pseudogene lncRNA, indicating evolutionary conservation. Our data highlight the biological relevance of rapidly evolving lncRNAs that infiltrate into central epigenetic regulatory circuits in vertebrate cells.
Collapse
Affiliation(s)
- Michele Scarola
- Laboratorio Nazionale-Consorzio Interuniversitario per le Biotecnologie, Laboratorio Nazionale (LNCIB), Padriciano 99, 34149, Trieste, Italy
- Dipartimento di Area Medica (DAME), Università degli Studi di Udine, p.le Kolbe 4, 33100, Udine, Italy
| | - Elisa Comisso
- Laboratorio Nazionale-Consorzio Interuniversitario per le Biotecnologie, Laboratorio Nazionale (LNCIB), Padriciano 99, 34149, Trieste, Italy
- Dipartimento di Area Medica (DAME), Università degli Studi di Udine, p.le Kolbe 4, 33100, Udine, Italy
| | - Massimo Rosso
- Laboratorio Nazionale-Consorzio Interuniversitario per le Biotecnologie, Laboratorio Nazionale (LNCIB), Padriciano 99, 34149, Trieste, Italy
- Dipartimento di Science della Vita, Università degli Studi di Trieste, Via E. Weiss 2, 34127, Trieste, Italy
| | - Giannino Del Sal
- Laboratorio Nazionale-Consorzio Interuniversitario per le Biotecnologie, Laboratorio Nazionale (LNCIB), Padriciano 99, 34149, Trieste, Italy
- Dipartimento di Science della Vita, Università degli Studi di Trieste, Via E. Weiss 2, 34127, Trieste, Italy
| | - Claudio Schneider
- Laboratorio Nazionale-Consorzio Interuniversitario per le Biotecnologie, Laboratorio Nazionale (LNCIB), Padriciano 99, 34149, Trieste, Italy
- Dipartimento di Area Medica (DAME), Università degli Studi di Udine, p.le Kolbe 4, 33100, Udine, Italy
| | - Stefan Schoeftner
- Laboratorio Nazionale-Consorzio Interuniversitario per le Biotecnologie, Laboratorio Nazionale (LNCIB), Padriciano 99, 34149, Trieste, Italy.
- Dipartimento di Science della Vita, Università degli Studi di Trieste, Via E. Weiss 2, 34127, Trieste, Italy.
| | - Roberta Benetti
- Laboratorio Nazionale-Consorzio Interuniversitario per le Biotecnologie, Laboratorio Nazionale (LNCIB), Padriciano 99, 34149, Trieste, Italy.
- Dipartimento di Area Medica (DAME), Università degli Studi di Udine, p.le Kolbe 4, 33100, Udine, Italy.
| |
Collapse
|
|
38
|
Radiotherapy-Resistant Breast Cancer Cells Enhance Tumor Progression by Enhancing Premetastatic Niche Formation through the HIF-1α-LOX Axis. Int J Mol Sci 2020; 21:ijms21218027. [PMID: 33126606 PMCID: PMC7663097 DOI: 10.3390/ijms21218027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/26/2020] [Accepted: 10/27/2020] [Indexed: 01/05/2023] Open
Abstract
Cancer stem cells (CSCs) exist in solid tumors and contribute to therapeutic resistance and disease recurrence. Previously, we reported that radiotherapy-resistant (RT-R)-MDA-MB-231 cells from highly metastatic MDA-MB-231 cells produced more CSCs than any other RT-R-breast cancer cells and showed therapeutic resistance and enhanced invasiveness. Hypoxia inducible factor-1α (HIF-1α) induced in the tumor microenvironment leads to the release of lysyl oxidase (LOX), which mediates collagen crosslinking at distant sites to facilitate environmental changes that allow cancer cells to easily metastasize. Therefore, in this study, we investigated whether RT-R-MDA-MB-231 cells induce greater HIF-1α expression, LOX secretion, and premetastatic niche formation than MDA-MB-231 cells do. RT-R-MDA-MB-231 cells increased HIF-1α expression and LOX secretion compared with MDA-MB-231 cells. Mice harboring RT-R-MDA-MB-231 cell xenografts showed enhanced tumor growth and higher expression of the CSC markers, CD44, Notch-4, and Oct3/4. In addition, mice injected with RT-R-MDA-MB-231 cells exhibited a higher level of HIF-1α in tumor tissue, increased secretion of LOX in plasma, higher induced levels of crosslinked collagen, and a higher population of CD11b+ BMDC recruitment around lung tissue, compared with those injected with MDA-MB-231 cells. These results suggest that RT-R-MDA-MB-231 cells contribute to tumor progression by enhancing premetastatic niche formation through the HIF-1α-LOX axis.
Collapse
|
|
39
|
Kim DK, Song B, Han S, Jang H, Bae SH, Kim HY, Lee SH, Lee S, Kim JK, Kim HS, Hong KM, Lee BI, Youn HD, Kim SY, Kang SW, Jang H. Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation. Cancers (Basel) 2020; 12:cancers12092601. [PMID: 32932964 PMCID: PMC7565739 DOI: 10.3390/cancers12092601] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/09/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Octamer-binding transcription factor 4 (OCT4) plays an important role in early embryonic development, but is rarely expressed in adults. However, in many cancer cells, this gene is re-expressed, making the cancer malignant. This present study revealed that inhibiting OCT4 transcriptional activity induces cancer cell differentiation and growth retardation. Specifically, when the phosphorylation of OCT4 serine 236 increases by interfering with the binding of protein phosphatase 1 (PP1) to OCT4, OCT4 loses its transcriptional activity and cancer cells differentiate. Therefore, this study presents the basis for the development of protein-protein interaction inhibitors that inhibit the binding of OCT4 and PP1 for cancer treatment. Abstract Octamer-binding transcription factor 4 (Oct4) plays an important role in maintaining pluripotency in embryonic stem cells and is closely related to the malignancies of various cancers. Although posttranslational modifications of Oct4 have been widely studied, most of these have not yet been fully characterized, especially in cancer. In this study, we investigated the role of phosphorylation of serine 236 of OCT4 [OCT4 (S236)] in human germ cell tumors (GCTs). OCT4 was phosphorylated at S236 in a cell cycle-dependent manner in a patient sample and GCT cell lines. The substitution of endogenous OCT4 by a mimic of phosphorylated OCT4 with a serine-to-aspartate mutation at S236 (S236D) resulted in tumor cell differentiation, growth retardation, and inhibition of tumor sphere formation. GCT cells expressing OCT4 S236D instead of endogenous OCT4 were similar to cells with OCT4 depletion at the mRNA transcript level as well as in the phenotype. OCT4 S236D also induced tumor cell differentiation and growth retardation in mouse xenograft experiments. Inhibition of protein phosphatase 1 by chemicals or short hairpin RNAs increased phosphorylation at OCT4 (S236) and resulted in the differentiation of GCTs. These results reveal the role of OCT4 (S236) phosphorylation in GCTs and suggest a new strategy for suppressing OCT4 in cancer.
Collapse
Affiliation(s)
- Dong Keon Kim
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
| | - Bomin Song
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
- Department of Life Science, Ewha Womans University, Seoul 03760, Korea;
| | - Suji Han
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
| | - Hansol Jang
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Seung-Hyun Bae
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Hee Yeon Kim
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
- Department of Life Science, Ewha Womans University, Seoul 03760, Korea;
| | - Seon-Hyeong Lee
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
| | - Seungjin Lee
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Jong Kwang Kim
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
| | - Han-Seong Kim
- Department of Pathology, Inje University Ilsan Paik Hospital, Goyang 10308, Korea;
| | - Kyeong-Man Hong
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
| | - Byung Il Lee
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Hong-Duk Youn
- National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080; Korea;
| | - Soo-Youl Kim
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
| | - Sang Won Kang
- Department of Life Science, Ewha Womans University, Seoul 03760, Korea;
| | - Hyonchol Jang
- Research Institute, National Cancer Center, Goyang 10408, Korea; (D.K.K.); (B.S.); (S.H.); (H.J.); (S.-H.B.); (H.Y.K.); (S.-H.L.); (S.L.); (J.K.K.); (K.-M.H.); (B.I.L.); (S.-Y.K.)
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea
- Correspondence: ; Tel.: +82-31-920-2239
| |
Collapse
|
|
40
|
Tegginamani AS, Shivakumar VH, Kallarakkal TG, Ismail SM, Abraham MT, Bin Zamzuri AT. Analysis of octamer-binding transcription factor-4 expression in oral leukoplakia. J Oral Maxillofac Pathol 2020; 24:400. [PMID: 33456258 PMCID: PMC7802831 DOI: 10.4103/jomfp.jomfp_272_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 06/12/2020] [Accepted: 06/24/2020] [Indexed: 11/14/2022] Open
Abstract
Background: Oral potentially malignant disorders have a risk for malignant transformation but are difficult to reliably identify and predict which patients are at the risk for malignant transformation. OCT4 has been hypothesized to play a key oncogenic driver in a variety of solid tumors. A deeper understanding of the aberrant molecular pathways which lead to carcinogenesis needs to be identified by the potential markers. Aims: To assess the OCT4 stemness factor in oral leukoplakia for its potential risk to malignant transformation. Settings and Design: 20 cases of oral leukoplakia were obtained from archives at Oral Cancer Research & Coordinating center (OCRCC) Malaysia Subjects and Methods: 20 cases of oral leukoplakia were assessed by OCT4 immunohistochemically. Oral squamous cell carcinoma was used as a control. Result: no expression of OCT 4 was observed in any cases of oral leukoplakia. Conclusion: The molecular mechanisms of Oct4 regulation and in particular of its switch on and off in tissues depends upon its microenvironment, which makes it challenging in fundamental and applied research fields of regenerative medicine and cancer therapy. It's better that patients should undergo multiple biopsies for the early detection of malignant transformation with close follow-up during the first two to three years, a large amount of work remains to be done with multi-marker panel investigation, as cure rates have remained constant over three decades.
Collapse
|
|
41
|
Guan S, Wei J, Huang L, Wu L. Chemotherapy and chemo-resistance in nasopharyngeal carcinoma. Eur J Med Chem 2020; 207:112758. [PMID: 32858472 DOI: 10.1016/j.ejmech.2020.112758] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 08/09/2020] [Accepted: 08/11/2020] [Indexed: 02/06/2023]
Abstract
Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) and occurs frequently in the south of China and Southeast Asian countries. Concurrent chemo-radiotherapy is one of the main treatments for NPC. Although, the combined treatment of chemo-radiotherapy produces a satisfying survival rate, the chemo-resistance arises as a big obstacle in curing recurrent NPC patients. The acquirement of chemo-resistance is usually along with a poor prognosis. So far, the mechanism of chemo-resistance in NPC has not been fully elucidated and there have not been a comprehensive review on this issue. Thus, it is of great significance to summarize the mechanisms involved in NPC chemo-resistance. In this review, the importance and limitations of chemotherapy and the mechanisms of chemo-resistances in NPC were discussed.
Collapse
Affiliation(s)
- Shuzhen Guan
- Medical College of Guangxi University, Nanning, 530004, China
| | - Jinrui Wei
- Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, PR China
| | - Lingkun Huang
- Medical College of Guangxi University, Nanning, 530004, China
| | - Lichuan Wu
- Medical College of Guangxi University, Nanning, 530004, China.
| |
Collapse
|
|
42
|
Mechanisms of cancer stem cell therapy. Clin Chim Acta 2020; 510:581-592. [PMID: 32791136 DOI: 10.1016/j.cca.2020.08.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/01/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are responsible for carcinogenesis and tumorigenesis and are involved in drug and radiation resistance, metastasis, tumor relapse and initiation. Remarkably, they have other abilities such as inheritance of self-renewal and de-differentiation. Hence, targeting CSCs is considered a potential anti-cancer therapeutic strategy. Recent advances in the identification of biomarkers to recognize CSCs and the development of new techniques to evaluate tumorigenic and carcinogenic roles of CSCs are instrumental to this approach. Elucidation of signaling pathways that regulate CSCs colony progression and drug resistance are critical in establishing effective targeted therapies. CSCs play a central key role in immunomodulation, immune evasion and effector immunity, which alters immune system balancing. These include mTOR, SHH, NOTCH and Wnt/β-catering in cancer progression. In this review article, we discuss the importance of these CSCs pathways in cancer therapy.
Collapse
|
|
43
|
Jariyal H, Gupta C, Bhat VS, Wagh JR, Srivastava A. Advancements in Cancer Stem Cell Isolation and Characterization. Stem Cell Rev Rep 2020; 15:755-773. [PMID: 31863337 DOI: 10.1007/s12015-019-09912-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Occurrence of stem cells (CSCs) in cancer is well established in last two decades. These rare cells share several properties including presence of common surface markers, stem cell markers, chemo- and radio- resistance and are highly metastatic in nature; thus, considered as valuable prognostic and therapeutic targets in cancer. However, the studies related to CSCs pave number of issues due to rare cell population and difficulties in their isolation ascribed to common stem cell marker. Various techniques including flow cytometry, laser micro-dissection, fluorescent nanodiamonds and microfluidics are used for the isolation of these rare cells. In this review, we have included the advance strategies adopted for the isolation of CSCs using above mentioned techniques. Furthermore, CSCs are primarily found in the core of the solid tumors and their microenvironment plays an important role in maintenance, self-renewal, division and tumor development. Therefore, in vivo tracking and model development become obligatory for functional studies of CSCs. Fluorescence and bioluminescence tagging has been widely used for transplantation assay and lineage tracking experiments to improve our understanding towards CSCs behaviour in their niche. Techniques such as Magnetic resonance imaging (MRI) and Positron emission tomography (PET) have proved useful for tracking of endogenous CSCs which could be helpful in their identification in clinical settings.
Collapse
Affiliation(s)
- Heena Jariyal
- Department of Biotechnology, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Chanchal Gupta
- Department of Biotechnology, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Vedika Sandeep Bhat
- Department of Biotechnology, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Jayant Ramakant Wagh
- Department of Biotechnology, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Akshay Srivastava
- Department of Medical Device, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India.
| |
Collapse
|
|
44
|
Kilmister EJ, Patel J, van Schaijik B, Bockett N, Brasch HD, Paterson E, Sim D, Davis PF, Roth IM, Itinteang T, Tan ST. Cancer Stem Cell Subpopulations Are Present Within Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma. Front Oncol 2020; 10:1091. [PMID: 32850316 PMCID: PMC7406827 DOI: 10.3389/fonc.2020.01091] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) have been identified in many cancer types including primary head and neck cutaneous squamous cell carcinoma (HNcSCC). This study aimed to identify and characterize CSCs in metastatic HNcSCC (mHNcSCC). Immunohistochemical staining performed on mHNcSCC samples from 15 patients demonstrated expression of the induced pluripotent stem cell (iPSC) markers OCT4, SOX2, NANOG, KLF4, and c-MYC in all 15 samples. In situ hybridization and RT-qPCR performed on four of these mHNcSCC tissue samples confirmed transcript expression of all five iPSC markers. Immunofluorescence staining performed on three of these mHNcSCC samples demonstrated expression of c-MYC on cells within the tumor nests (TNs) and the peri-tumoral stroma (PTS) that also expressed KLF4. OCT4 was expressed on the SOX2+/NANOG+/KLF4+ cells within the TNs, and the SOX2+/NANOG+/KLF4+ cells within the PTS. RT-qPCR demonstrated transcript expression of all five iPSC markers in all three mHNcSCC-derived primary cell lines, except for SOX2 in one cell line. Western blotting showed the presence of SOX2, KLF4, and c-MYC but not OCT4 and NANOG in the three mHNcSCC-derived primary cell lines. All three cell lines formed tumorspheres, at the first passage. We demonstrated an OCT4+/NANOG+/SOX2+/KLF4+/c-MYC+ CSC subpopulation and an OCT4+/NANOG-/SOX2+/KLF4+/c-MYC+ subpopulation within the TNs, and an OCT4+/NANOG+/SOX2+/KLF4+/c-MYC+ subpopulation within the PTS of mHNcSCC.
Collapse
Affiliation(s)
| | - Josie Patel
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | | | | | - Helen D Brasch
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Erin Paterson
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Dalice Sim
- Biostatistical Group/Dean's Department, University of Otago, Wellington, New Zealand
| | - Paul F Davis
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Imogen M Roth
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | | | - Swee T Tan
- Gillies McIndoe Research Institute, Wellington, New Zealand.,Wellington Regional Plastic, Maxillofacial and Burns Unit, Hutt Hospital, Wellington, New Zealand.,Department of Surgery, The University of Melbourne, Parkville, VIC, Australia
| |
Collapse
|
|
45
|
Huang T, Song X, Xu D, Tiek D, Goenka A, Wu B, Sastry N, Hu B, Cheng SY. Stem cell programs in cancer initiation, progression, and therapy resistance. Am J Cancer Res 2020; 10:8721-8743. [PMID: 32754274 PMCID: PMC7392012 DOI: 10.7150/thno.41648] [Citation(s) in RCA: 278] [Impact Index Per Article: 55.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 04/09/2020] [Indexed: 12/13/2022] Open
Abstract
Over the past few decades, substantial evidence has convincingly revealed the existence of cancer stem cells (CSCs) as a minor subpopulation in cancers, contributing to an aberrantly high degree of cellular heterogeneity within the tumor. CSCs are functionally defined by their abilities of self-renewal and differentiation, often in response to cues from their microenvironment. Biological phenotypes of CSCs are regulated by the integrated transcriptional, post-transcriptional, metabolic, and epigenetic regulatory networks. CSCs contribute to tumor progression, therapeutic resistance, and disease recurrence through their sustained proliferation, invasion into normal tissue, promotion of angiogenesis, evasion of the immune system, and resistance to conventional anticancer therapies. Therefore, elucidation of the molecular mechanisms that drive cancer stem cell maintenance, plasticity, and therapeutic resistance will enhance our ability to improve the effectiveness of targeted therapies for CSCs. In this review, we highlight the key features and mechanisms that regulate CSC function in tumor initiation, progression, and therapy resistance. We discuss factors for CSC therapeutic resistance, such as quiescence, induction of epithelial-to-mesenchymal transition (EMT), and resistance to DNA damage-induced cell death. We evaluate therapeutic approaches for eliminating therapy-resistant CSC subpopulations, including anticancer drugs that target key CSC signaling pathways and cell surface markers, viral therapies, the awakening of quiescent CSCs, and immunotherapy. We also assess the impact of new technologies, such as single-cell sequencing and CRISPR-Cas9 screening, on the investigation of the biological properties of CSCs. Moreover, challenges remain to be addressed in the coming years, including experimental approaches for investigating CSCs and obstacles in therapeutic targeting of CSCs.
Collapse
|
|
46
|
Kim DC, Jin H, Lee JS, Son E, Lee GW, Kim HJ. P2Y 2R has a significant correlation with Notch-4 in patients with breast cancer. Oncol Lett 2020; 20:647-654. [PMID: 32565989 PMCID: PMC7286009 DOI: 10.3892/ol.2020.11630] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/08/2020] [Indexed: 01/01/2023] Open
Abstract
Our previous study found that highly metastatic breast cancer cells, such as MDA-MB-231 cells, release higher levels of ATP and exhibit greater P2Y2 receptor (P2Y2R) activity than lowly metastatic breast cancer cells, and that P2Y2R activation mediated by ATP plays a significant role in tumor progression and metastasis. In addition, we reported that radiotherapy-resistant (RT-R) breast cancer cells promote invasion and tumor growth through the activation of P2Y2R by ATP released from RT-R-breast cancer cells than breast cancer cells. Moreover, increased numbers of cancer stem cells (CSCs) were observed among the RT-R-breast cancer cell population. Therefore, in this study, we investigated the expression level of five CSC markers (CD24, CD44, Oct3/4, Notch-4 and ALDH1A1) as well as P2Y2R in the tumor tissues of patients with breast cancer and determined which CSC marker correlates with P2Y2R in breast cancer. According to the immunohistochemical analysis, CD44, Oct3/4 and Notch-4 but not ALDH1A1 were significantly expressed in the tumor tissues (n=180) compared with the normal epithelial tissues (n=20) of patients with breast cancer. It was demonstrated that P2Y2R expression was increased in tumor tissues of patients with breast cancer compared with normal epithelial tissue. Notably, it was identified that P2Y2R expression has a significant correlation with only the CSC marker Notch-4 in patients with breast cancer. The results of this study suggested for the first time to the best of our knowledge that Notch-4 has a notable correlation with P2Y2R, which has important roles in tumor progression and metastasis.
Collapse
Affiliation(s)
- Dong Chul Kim
- Department of Pathology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, South Gyeongsang 52727, Republic of Korea
| | - Hana Jin
- Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, South Gyeongsang 52727, Republic of Korea
| | - Jong Sil Lee
- Department of Pathology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, South Gyeongsang 52727, Republic of Korea
| | - Euna Son
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, South Gyeongsang 52828, Republic of Korea
| | - Gyeong Won Lee
- Division of Hematology-Oncology, Department of Internal Medicine, College of Medicine, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, South Gyeongsang 52727, Republic of Korea
| | - Hye Jung Kim
- Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, South Gyeongsang 52727, Republic of Korea
| |
Collapse
|
|
47
|
Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers. PLoS Pathog 2020; 16:e1008468. [PMID: 32298395 PMCID: PMC7228134 DOI: 10.1371/journal.ppat.1008468] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 05/15/2020] [Accepted: 03/09/2020] [Indexed: 12/12/2022] Open
Abstract
Octamer binding transcription factor-4 (Oct4), is highly expressed in stem cells and has indispensable roles in pluripotency and cellular reprogramming. In contrast to other factors used for cellular reprogramming, a role for Oct4 outside embryonic stem cells has been elusive and highly controversial. Emerging evidence implicates Oct4 in the carcinogenic process, but the mechanism through which Oct4 may be functioning in cancers is not fully appreciated. Here, we provide evidence that Oct4 is expressed in human cervical cancer and this expression correlates with the presence of the human papillomavirus (HPV) oncogenes E6 and E7. Surprisingly, the viral oncogenes can complement exogenously provided Oct4 in reprogramming assays, providing functional validation for their ability to activate Oct4 transcription in Mouse Embryonic Fibroblasts (MEFs). To interrogate potential roles of Oct4 in cervical cancers we knocked-down Oct4 in HPV(+) (HeLa & CaSki) and HPV(-) (C33A) cervical cancer cell lines and found that Oct4 knockdown attenuated clonogenesis, only in the HPV(+) cells. More unexpectedly, cell proliferation and migration, were differentially affected in HPV(+) and HPV(-) cell lines. We provide evidence that Oct4 interacts with HPV E7 specifically at the CR3 region of the E7 protein and that introduction of the HPV oncogenes in C33A cells and human immortalised keratinocytes generates Oct4-associated transcriptional and phenotypic patterns, which mimic those seen in HPV(+) cells. We propose that a physical interaction of Oct4 with E7 regulates its activity in HPV(+) cervical cancers in a manner not seen in other cancer types.
Collapse
|
|
48
|
Xie J, Lin LS, Huang XY, Gan RH, Ding LC, Su BH, Zhao Y, Lu YG, Zheng DL. The NOTCH1-HEY1 pathway regulates self-renewal and epithelial-mesenchymal transition of salivary adenoid cystic carcinoma cells. Int J Biol Sci 2020; 16:598-610. [PMID: 32025208 PMCID: PMC6990919 DOI: 10.7150/ijbs.36407] [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: 05/06/2019] [Accepted: 11/12/2019] [Indexed: 12/13/2022] Open
Abstract
Our previous study demonstrated a close relationship between the NOTCH signaling pathway and salivary adenoid cystic carcinoma (SACC). Its receptor gene, NOTCH1, and its downstream gene, HES1, contribute to the proliferation, invasion and metastasis of SACC. Accumulating evidence supports HEY1 as another effector of the signaling pathway. The purpose of this study was to explore the effects of the NOTCH1-HEY1 pathway on the proliferation, invasion and metastasis of SACC cells. Our results verified that HEY1 is a specific molecular target of the NOTCH signaling pathway in SACC cells and that its expression in carcinoma is much higher than that in paracarcinoma tissues. The expression of NOTCH1 and HEY1 are positively correlated in the salivary adenoid cystic carcinoma tissues. NOTCH1 is significantly related to the activation of HEY1 in SACC, and that HEY1 reciprocally regulates NOTCH1 expression in SACC. HEY1 promotes cell proliferation and spheroid formation and inhibits cell apoptosis in vitro. In addition, HEY1 enhances the tumorigenicity of SACC in vivo. Furthermore, HEY1 increases cell invasion and metastasis by driving the expression of epithelial-mesenchymal transition (EMT)-related genes and MMPs. The results of this study indicate that the NOTCH1-HEY1 pathway is specifically upregulated in SACC and promotes cell proliferation, self-renewal, invasion, metastasis and the expression of EMT-related genes and MMPs. Our findings suggest that a NOTCH1-HEY1 pathway inhibitor might therefore have potential therapeutic applications in treating SACC patients by inhibiting cancer cell growth and metastasis.
Collapse
Affiliation(s)
- Jing Xie
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China.,Key laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou 350004, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou 350122, China
| | - Li-Song Lin
- Department of Oral and Maxillofacial Surgery, Affiliated First Hospital of Fujian Medical University, 20 Cha Zhong Road, Fuzhou 350005, China
| | - Xiao-Yu Huang
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China.,Key laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou 350004, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou 350122, China
| | - Rui-Huan Gan
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China.,Key laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou 350004, China
| | - Lin-Can Ding
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China
| | - Bo-Hua Su
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China
| | - Yong Zhao
- Key laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou 350004, China.,Department of pathology, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China
| | - You-Guang Lu
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou 350000, China.,Key laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou 350004, China
| | - Da-Li Zheng
- Key laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou 350004, China
| |
Collapse
|
|
49
|
Kilic A, Barlak N, Sanli F, Aytatli A, Capik O, Karatas OF. Mode of action of carboplatin via activating p53/miR‐145 axis in head and neck cancers. Laryngoscope 2019; 130:2818-2824. [DOI: 10.1002/lary.28492] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/06/2019] [Accepted: 12/10/2019] [Indexed: 12/13/2022]
|
|
50
|
Yin X, Yang S, Zhang M, Yue Y. The role and prospect of JMJD3 in stem cells and cancer. Biomed Pharmacother 2019; 118:109384. [PMID: 31545292 DOI: 10.1016/j.biopha.2019.109384] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 08/12/2019] [Accepted: 08/22/2019] [Indexed: 12/11/2022] Open
Abstract
Currently, stem cells are reported to be involved in tumor formation, drug resistance and recurrence. Inhibiting the proliferation of tumor cells, promoting their senescence and apoptosis has been the most important anti-tumor therapy. Epigenetics is involved in the regulation of gene expression and is closely related to cancer and stem cells. It mainly includes DNA methylation, histone modification, and chromatin remodeling. Histone methylation and demethylation play an important role in histone modification. Histone 3 lysine 27 trimethylation (H3K27me3) induces transcriptional inhibition and plays an important role in gene expression. Jumonji domain-containing protein-3 (JMJD3), one of the demethyases of histone H3K27me3, has been reported to be associated with the prognosis of many cancers and stem cells differentiation. Inhibition of JMJD3 can reduce proliferation and promote apoptosis in tumor cells, as well as suppress differentiation in stem cells. GSK-J4 is an inhibitor of demethylase JMJD3 and UTX, which has been shown to possess anti-cancer and inhibition of embryonic stem cells differentiation effects. In this review, we examine how JMJD3 regulates cellular fates of stem cells and cancer cells and references were identified through searches of PubMed, Medline, Web of Science.
Collapse
Affiliation(s)
- Xiaojiao Yin
- Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun 130000, China
| | - Siyu Yang
- Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun 130000, China
| | - Mingyue Zhang
- Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun 130000, China
| | - Ying Yue
- Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun 130000, China.
| |
Collapse
|