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1
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Nakamura N, Sato-Dahlman M, Travis E, Jacobsen K, Yamamoto M. CDX2 Promoter-Controlled Oncolytic Adenovirus Suppresses Tumor Growth and Liver Metastasis of Colorectal Cancer. Cancer Sci 2025. [PMID: 40275626 DOI: 10.1111/cas.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/03/2025] [Accepted: 03/15/2025] [Indexed: 04/26/2025] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, and liver metastasis (CRLM) is the most common among its distant metastases. We have recently generated a CDX2 promoter-controlled oncolytic adenovirus (Ad5/3-pCDX2) that showed an anticancer effect for CDX2-positive upper gastrointestinal tumors. Here, we reported the anticancer effect of Ad5/3-pCDX2 for CDX2-positive CRC and CRLM, and its combination efficacy with 5-fluorouracil (5FU) in vitro and in vivo. We used HT29 as CDX2-positive, and LS174T and SW480 as CDX2-negative CRC cell lines. Without 5FU, Ad5/3-pCDX2 killed HT29 but not LS174T and SW480 cells. In vitro, 5FU exposure upregulated CDX2 mRNA levels in all three cell lines. The 5FU combination enhanced the cytocidal effect and virus replication of Ad5/3-pCDX2 in CDX2-negative LS174T. In mouse xenograft models, Ad5/3-pCDX2 monotherapy suppressed the HT29 subcutaneous tumor growth compared to the control group. The 5FU plus Ad5/3-pCDX2 combination therapy showed a remarkable antitumor effect over the efficacy of Ad5/3-pCDX2 monotherapy. In the LS174T subcutaneous tumor, although Ad5/3-pCDX2 monotherapy did not show an antitumor effect, the 5FU plus Ad5/3-pCDX2 combination therapy significantly suppressed the tumor growth compared to the Ad5/3-pCDX2 monotherapy. In mice with HT29 liver metastasis, intrasplenic injection of Ad5/3-pCDX2 induced virus replication in liver tumors and thus successfully attenuated tumor growth. In conclusion, Ad5/3-pCDX2 showed a significant anticancer effect that was enhanced by 5FU treatment in not only CDX2-positive but also negative CRCs. Ad5/3-pCDX2 is a promising therapeutic modality for metastatic CRC such as CRLM.
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Affiliation(s)
- Naohiko Nakamura
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mizuho Sato-Dahlman
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Elise Travis
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kari Jacobsen
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Masato Yamamoto
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
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2
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Elmi M, Dass JH, Dass CR. Current treatments for oropharyngeal squamous cell carcinoma and the move towards molecular therapy. J Pharm Pharmacol 2024; 76:1552-1562. [PMID: 39137149 DOI: 10.1093/jpp/rgae107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 07/25/2024] [Indexed: 08/15/2024]
Abstract
OBJECTIVES In this review, we discuss oropharyngeal squamous cell carcinoma (OPSCC) treatment options with a focus on the molecular mechanisms of OPSCC in head and neck squamous cell carcinoma (HNSCC) and head and neck cancers (HNCs). Treatment can be radical intent (aim for cure) or palliative intent (aim for disease control and symptom management). OPSCC is a prominent subset of HNSCCs in Australia and the Western World. METHOD We looked at the current conventional treatment options with an overview of recent advances and future endeavours. KEY FINDINGS We identified that radiotherapy is the primary management for OPSCC in most countries, including the USA, UK, NZ, and Australia. In contrast, surgery is only considered for superficial OPSCC or neck surgery. If surgery is incomplete, then definitive management still requires radiotherapy. CONCLUSION Molecular therapy is largely at the preclinical stage, with cetuximab, nivolumab, pembrolizumab, Lenvatinib, and bevacizumab being tested clinically currently.
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Affiliation(s)
- Mitra Elmi
- Curtin Medical School, Curtin University, Perth, WA, Australia
- Curtin Health Innovation Research Institute, Perth, WA, Australia
| | - Joshua H Dass
- Curtin Medical School, Curtin University, Perth, WA, Australia
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Crispin R Dass
- Curtin Medical School, Curtin University, Perth, WA, Australia
- Curtin Health Innovation Research Institute, Perth, WA, Australia
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3
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Obara P, Wolski P, Pańczyk T. Insights into the Molecular Structure, Stability, and Biological Significance of Non-Canonical DNA Forms, with a Focus on G-Quadruplexes and i-Motifs. Molecules 2024; 29:4683. [PMID: 39407611 PMCID: PMC11477922 DOI: 10.3390/molecules29194683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/27/2024] [Accepted: 09/30/2024] [Indexed: 10/20/2024] Open
Abstract
This article provides a comprehensive examination of non-canonical DNA structures, particularly focusing on G-quadruplexes (G4s) and i-motifs. G-quadruplexes, four-stranded structures formed by guanine-rich sequences, are stabilized by Hoogsteen hydrogen bonds and monovalent cations like potassium. These structures exhibit diverse topologies and are implicated in critical genomic regions such as telomeres and promoter regions of oncogenes, playing significant roles in gene expression regulation, genome stability, and cellular aging. I-motifs, formed by cytosine-rich sequences under acidic conditions and stabilized by hemiprotonated cytosine-cytosine (C:C+) base pairs, also contribute to gene regulation despite being less prevalent than G4s. This review highlights the factors influencing the stability and dynamics of these structures, including sequence composition, ionic conditions, and environmental pH. Molecular dynamics simulations and high-resolution structural techniques have been pivotal in advancing our understanding of their folding and unfolding mechanisms. Additionally, the article discusses the therapeutic potential of small molecules designed to selectively bind and stabilize G4s and i-motifs, with promising implications for cancer treatment. Furthermore, the structural properties of these DNA forms are explored for applications in nanotechnology and molecular devices. Despite significant progress, challenges remain in observing these structures in vivo and fully elucidating their biological functions. The review underscores the importance of continued research to uncover new insights into the genomic roles of G4s and i-motifs and their potential applications in medicine and technology. This ongoing research promises exciting developments in both basic science and applied fields, emphasizing the relevance and future prospects of these intriguing DNA structures.
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Affiliation(s)
| | | | - Tomasz Pańczyk
- Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, ul. Niezapominajek 8, 30239 Cracow, Poland; (P.O.); (P.W.)
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4
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Bortoletto S, Nunes-Souza E, Marchi R, Ruthes MO, Okano LM, Tofolo MV, Centa A, Fonseca AS, Rosolen D, Cavalli LR. MicroRNAs role in telomere length maintenance and telomerase activity in tumor cells. J Mol Med (Berl) 2024; 102:1089-1100. [PMID: 39042290 DOI: 10.1007/s00109-024-02467-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/24/2024]
Abstract
MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.
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Affiliation(s)
- Stéfanne Bortoletto
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil
| | - Emanuelle Nunes-Souza
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil
| | - Rafael Marchi
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil
| | - Mayara Oliveira Ruthes
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil
| | - Larissa M Okano
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil
| | - Maria Vitoria Tofolo
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil
| | - Ariana Centa
- Universidade Alto Vale do Rio do Peixe (UNIARP), Caçador, SC, Brazil
| | - Aline S Fonseca
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil
| | - Daiane Rosolen
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil
| | - Luciane R Cavalli
- Faculdades Pequeno Príncipe, Research Institute Pelé Pequeno Príncipe, Curitiba, PR, Brazil.
- Oncology Department, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
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5
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Yeh TJ, Luo CW, Du JS, Huang CT, Wang MH, Chuang TM, Gau YC, Cho SF, Liu YC, Hsiao HH, Chen LT, Pan MR, Wang HC, Moi SH. Deciphering the Functions of Telomerase Reverse Transcriptase in Head and Neck Cancer. Biomedicines 2023; 11:691. [PMID: 36979671 PMCID: PMC10044978 DOI: 10.3390/biomedicines11030691] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 02/19/2023] [Accepted: 02/22/2023] [Indexed: 03/30/2023] Open
Abstract
Head and neck cancers (HNCs) are among the ten leading malignancies worldwide. Despite significant progress in all therapeutic modalities, predictive biomarkers, and targeted therapies for HNCs are limited and the survival rate is unsatisfactory. The importance of telomere maintenance via telomerase reactivation in carcinogenesis has been demonstrated in recent decades. Several mechanisms could activate telomerase reverse transcriptase (TERT), the most common of which is promoter alternation. Two major hotspot TERT promoter mutations (C228T and C250T) have been reported in different malignancies such as melanoma, genitourinary cancers, CNS tumors, hepatocellular carcinoma, thyroid cancers, sarcomas, and HNCs. The frequencies of TERT promoter mutations vary widely across tumors and is quite high in HNCs (11.9-64.7%). These mutations have been reported to be more enriched in oral cavity SCCs and HPV-negative tumors. The association between TERT promoter mutations and poor survival has also been demonstrated. Till now, several therapeutic strategies targeting telomerase have been developed although only a few drugs have been used in clinical trials. Here, we briefly review and summarize our current understanding and evidence of TERT promoter mutations in HNC patients.
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Affiliation(s)
- Tsung-Jang Yeh
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chi-Wen Luo
- Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Jeng-Shiun Du
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chien-Tzu Huang
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Min-Hung Wang
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Tzer-Ming Chuang
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yuh-Ching Gau
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Shih-Feng Cho
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yi-Chang Liu
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Hui-Hua Hsiao
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Li-Tzong Chen
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
| | - Mei-Ren Pan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Hui-Ching Wang
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Sin-Hua Moi
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Oral Papillomatosis: Its Relation with Human Papilloma Virus Infection and Local Immunity—An Update. Medicina (B Aires) 2022; 58:medicina58081103. [PMID: 36013570 PMCID: PMC9415166 DOI: 10.3390/medicina58081103] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 11/16/2022] Open
Abstract
Oral papilloma lesions may appear as a result of HPV infection, or not, and only special molecular methods could differentiate them. Low-risk and high-risk HPV types could induce oral HPV papillomatosis with different natural evolution, clearance and persistence mechanisms. The pathogenic mechanisms are based on the crosstalk between the oral epithelial and immune cells and this very efficient virus. HPV acts as a direct inducer in the process of transforming a benign lesion into a malignant one, the cancerization process being also debated in this paper. According to the degree of malignity, three types of papillomatous lesions can be described in the oral cavity: benign lesions, potential malign disorders and malignant lesions. The precise molecular diagnostic is important to identify the presence of various virus types and also the virus products responsible for its oncogenicity. An accurate diagnostic of oral papilloma can be established through a good knowledge of etiological and epidemiological factors, clinical examination and laboratory tests. This review intends to update the pathogenic mechanisms driving the macroscopic and histological features of oral papillomatosis having HPV infection as the main etiological factor, focusing on its interreference in the local immunity. In the absence of an accurate molecular diagnostic and knowledge of local immunological conditions, the therapeutic strategy could be difficult to decide.
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7
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Novel Diagnostic Biomarkers in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23020852. [PMID: 35055034 PMCID: PMC8776048 DOI: 10.3390/ijms23020852] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.
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8
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Sun Z, Sun X, Chen Z, Du J, Wu Y. Head and Neck Squamous Cell Carcinoma: Risk Factors, Molecular Alterations, Immunology and Peptide Vaccines. Int J Pept Res Ther 2021; 28:19. [PMID: 34903958 PMCID: PMC8653808 DOI: 10.1007/s10989-021-10334-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2021] [Indexed: 12/29/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) arises from the epithelial lining of the oral cavity, hypopharynx, oropharynx, and larynx. There are several potential risk factors that cause the generation of HNSCC, including cigarette smoking, alcohol consumption, betel quid chewing, inadequate nutrition, poor oral hygiene, HPV and Epstein–Barr virus, and Candida albicans infections. HNSCC has causative links to both environmental factors and genetic mutations, with the latter playing a more critical role in cancer progression. These molecular changes to epithelial cells include the inactivation of cancer suppressor genes and proto-oncogenes overexpression, resulting in tumour cell proliferation and distant metastasis. HNSCC patients have impaired dendritic cell (DC) and natural killer (NK) cell functions, increased production of higher immune-suppressive molecules, loss of regulatory T cells and co-stimulatory molecules and major histocompatibility complex (MHC) class Ι molecules, lower number of lymphocyte subsets, and a poor response to antigen-presenting cells. At present, the standard treatment modalities for HNSCC patients include surgery, chemotherapy and radiotherapy, and combinatorial therapy. Despite advances in the development of novel treatment modalities over the last few decades, survival rates of HNSCC patients have not increased. To establish effective immunotherapies, a greater understanding of interactions between the immune system and HNSCC is required, and there is a particular need to develop novel therapeutic options. A therapeutic cancer vaccine has been proposed as a promising method to improve outcome by inducing a powerful adaptive immune response that leads to cancer cell elimination. Compared with other vaccines, peptide cancer vaccines are more robust and specific. In the past few years, there have been remarkable achievements in peptide-based vaccines for HNSCC patients. Here, we summarize the latest molecular alterations in HNSCC, explore the immune response to HNSCC, and discuss the latest developments in peptide-based cancer vaccine strategies. This review highlights areas for valuable future research focusing on peptide-based cancer vaccines.
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Affiliation(s)
- Zhe Sun
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
| | - Xiaodong Sun
- Department of Endodontics, Gaoxin Branch of Jinan Stomatological Hospital, Jinan, Shandong 250000 China
| | - Zhanwei Chen
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
| | - Juan Du
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
| | - Yihua Wu
- Department of Stomatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
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Herrero de la Parte B, Rodeño-Casado M, Iturrizaga Correcher S, Mar Medina C, García-Alonso I. Curcumin Reduces Colorectal Cancer Cell Proliferation and Migration and Slows In Vivo Growth of Liver Metastases in Rats. Biomedicines 2021; 9:biomedicines9091183. [PMID: 34572369 PMCID: PMC8467247 DOI: 10.3390/biomedicines9091183] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/20/2021] [Accepted: 09/05/2021] [Indexed: 12/22/2022] Open
Abstract
Background: New therapeutic approaches are an essential need for patients suffering from colorectal cancer liver metastases. Curcumin, a well-known plant-derived polyphenol, has been shown to play a role in the modulation of multiple signaling pathways involved in the development and progression of certain cancer cells in vitro. This study aims to assess the anti-tumor effect of curcumin on CC531 colorectal cancer cells, both in vitro and in vivo. Methods: On CC531 cultures, the cell viability and cell migration capacity were analyzed (wound healing test) 24, 48, and 72 h after treatment with curcumin (15, 20, 25, or 30 µM). Additionally, in WAG/RijHsd tumor-bearing rats, the total and individual liver lobe tumor volume was quantified in untreated and curcumin-treated animals (200 mg/kg/day, oral). Furthermore, serum enzyme measurements (GOT, GPT, glucose, bilirubin, etc.) were carried out to assess the possible effects on the liver function. Results: In vitro studies showed curcumin’s greatest effects 48h after application, when all of the tested doses reduced cell proliferation by more than 30%. At 72 h, the highest doses of curcumin (25 and 30 µM) reduced cell viability to less than 50%. The wound healing test also showed that curcumin inhibits migration capacity. In vivo, curcumin slowed down the tumor volume of liver implants by 5.6-fold (7.98 ± 1.45 vs. 1.41 ± 1.33; p > 0.0001). Conclusions: Curcumin has shown an anti-tumor effect against liver implants from colorectal cancer, both in vitro and in vivo, in this experimental model.
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Affiliation(s)
- Borja Herrero de la Parte
- Department of Surgery and Radiology and Physical Medicine, University of The Basque Country, ES48940 Leioa, Spain; (M.R.-C.); (I.G.-A.)
- Biocruces Bizkaia Health Research Institute, ES48903 Barakaldo, Spain
- Correspondence:
| | - Mikel Rodeño-Casado
- Department of Surgery and Radiology and Physical Medicine, University of The Basque Country, ES48940 Leioa, Spain; (M.R.-C.); (I.G.-A.)
| | - Sira Iturrizaga Correcher
- Department of Clinical Analyses, Osakidetza Basque Health Service, Galdakao-Usansolo Hospital, ES48960 Galdakao, Spain; (S.I.C.); (C.M.M.)
| | - Carmen Mar Medina
- Department of Clinical Analyses, Osakidetza Basque Health Service, Galdakao-Usansolo Hospital, ES48960 Galdakao, Spain; (S.I.C.); (C.M.M.)
| | - Ignacio García-Alonso
- Department of Surgery and Radiology and Physical Medicine, University of The Basque Country, ES48940 Leioa, Spain; (M.R.-C.); (I.G.-A.)
- Biocruces Bizkaia Health Research Institute, ES48903 Barakaldo, Spain
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10
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Rowaiye AB, Mendes YJT, Olofinsae SA, Oche JB, Oladipo OH, Okpalefe OA, Ogidigo JO. Camptothecin shows better promise than Curcumin in the inhibition of the Human Telomerase: A computational study. Heliyon 2021; 7:e07742. [PMID: 34485722 PMCID: PMC8405929 DOI: 10.1016/j.heliyon.2021.e07742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/17/2021] [Accepted: 08/05/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVES The Human Telomerase enzyme has become a drug target in the treatment of cancers and age-related disorders. This study aims to identify potential natural inhibitors of the Human Telomerase from compounds derived from edible African plants. MATERIALS AND METHODS A library of 1,126 natural compounds was molecularly docked against the Telomerase Reverse Transcriptase (PDB ID: 5ugw), the catalytic subunit of the target protein. Curcumin, a known Telomerase inhibitor was used as the standard. The front-runner compounds were screened for bioavailability, pharmacokinetic properties, and bioactivity using the SWISSADME, PKCSM, and Molinspiration webservers respectively. The molecular dynamic simulation and analyses of the apo and holo proteins were performed by the Galaxy supercomputing webserver. RESULTS The results of the molecular docking and virtual screening reveal Augustamine and Camptothecin as lead compounds. Augustamine has better drug-likeness and pharmacokinetic properties while Camptothecin showed better bioactivity and stronger binding affinity (-8.2 kcal/mol) with the target. The holo structure formed by Camptothecin showed greater inhibitory activity against the target with a total RMSF of 169.853, B-Factor of 20.164, and 108 anti-correlating residues. CONCLUSION Though they both act at the same binding site, Camptothecin induces greater Telomerase inhibition and better molecular stability than the standard, Curcumin. Further tests are required to investigate the inhibitory activities of the lead compounds.
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Affiliation(s)
| | | | - Samson Ayodeji Olofinsae
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria
| | | | | | | | - Joyce Oloaigbe Ogidigo
- Bioresources Development Centre, National Biotechnology Development Agency, Abuja, Nigeria
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11
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Kato T, Nakamori M, Matsumura S, Nakamura M, Ojima T, Fukuhara H, Ino Y, Todo T, Yamaue H. Oncolytic virotherapy with human telomerase reverse transcriptase promoter regulation enhances cytotoxic effects against gastric cancer. Oncol Lett 2021; 21:490. [PMID: 33968206 PMCID: PMC8100961 DOI: 10.3892/ol.2021.12751] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 03/18/2021] [Indexed: 12/19/2022] Open
Abstract
Currently, gastric cancer is the third most common cause of cancer-associated mortality worldwide. Oncolytic virotherapy using herpes simplex virus (HSV) has emerged as a novel therapeutic strategy against cancer. Telomerase is activated in >90of malignant tumors, including gastric cancer, and human telomerase reverse transcriptase (hTERT) is one of the major components of telomerase enzyme. Therefore, in oncolytic HSV, placing the essential genes under the regulation of the hTERT promoter may enhance its antitumor efficacy. The present study examined the antitumor effect of fourth-generation oncolytic HSVs, which contain the ICP6 gene under the regulation of the hTERT promoter (T-hTERT). To examine the association between hTERT expression and prognosis in patients with gastric cancer, immunohistochemical analysis of resected tumor specimens was performed. The enhanced efficacy of T-hTERT was determined in human gastric cancer cell lines in vitro and in human gastric adenocarcinoma specimens in vivo. In in vitro experiments, enhanced cytotoxicity of T-hTERT was observed in MKN1, MKN28 and MKN45 cells compared with that of a third-generation oncolytic HSV, T-null. In particular, the cytotoxicity of T-hTERT was markedly enhanced in MKN45 cells. Furthermore, in vivo experiments demonstrated that 36.7 and 54.9% of cells were found to be lysed 48 h after infection with T-null or T-hTERT viruses at 0.01 pfu/cell, respectively. The T-hTERT-treated group exhibited considerably lower cell viability than the control [phosphate-buffered saline (-)] group. Therefore, employing oncolytic HSVs that contain the ICP6 gene under the regulation of the hTERT promoter may be an effective therapeutic strategy for gastric cancer. To the best of our knowledge, the present study was the first to describe the effect of an oncolytic HSV with ICP6 expression regulated by the hTERT promoter on gastric cancer cells.
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Affiliation(s)
- Tomoya Kato
- Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama 641-8510, Japan
| | - Mikihito Nakamori
- Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama 641-8510, Japan
| | - Shuichi Matsumura
- Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama 641-8510, Japan
| | - Masaki Nakamura
- Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama 641-8510, Japan
| | - Toshiyasu Ojima
- Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama 641-8510, Japan
| | - Hiroshi Fukuhara
- Department of Urology, Kyorin University, School of Medicine, Mitaka, Tokyo 181-8611, Japan
| | - Yasushi Ino
- Division of Innovative Cancer Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Tomoki Todo
- Division of Innovative Cancer Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Hiroki Yamaue
- Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama 641-8510, Japan
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12
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Yi L, Kong J, Xiong Y, Yi S, Gan T, Huang C, Duan Y, Zhu X. Genome mining of Streptomyces sp. CB00271 as a natural high-producer of β-rubromycin and the resulting discovery of β-rubromycin acid. Biotechnol Bioeng 2021; 118:2243-2254. [PMID: 33629382 DOI: 10.1002/bit.27732] [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: 12/28/2020] [Revised: 02/18/2021] [Accepted: 02/22/2021] [Indexed: 11/06/2022]
Abstract
β-rubromycin (β-RUB) (1) is an efficient inhibitor of human telomerase possessing a unique spiroketal moiety as a potential pharmacophore and regarded as a promising anticancer drug lead. But the development of (β-RUB) (1) has long been hampered by its low titer and very poor water solubility. By adopting a genome mining strategy, an FAD-dependent monooxygenase RubN involving with the formation of the spiro system was applied as the probe and Streptomyces sp. CB00271 was screened out from our strain collection as an alternative natural high producer of β-RUB (1). After a series of fermentation optimizations, CB00271 could produce 124.8 ± 3.4 mg/L β-RUB (1), which was the highest titer up to now. Moreover, the enhanced production of β-RUB (1) in fermentation broth also led to the discovery of a new congener β-RUB acid (7), which was structurally elucidated as the acid form of β-RUB (1). Comparing to β-RUB (1), the substituted carboxyl group endowed β-RUB acid (7) much better solubility in serum and resulted in its higher activity towards tumor cells. Our work set up a solid base for the pilot-scale production of β-RUB (1) and its congeners to facilitate their future development as promising anticancer drug leads, and also provide an alternative and practical strategy for the exploitation of other important microbial natural products.
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Affiliation(s)
- Liwei Yi
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China
| | - Jieqian Kong
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China
| | - Yi Xiong
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China
| | - Sirui Yi
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China
| | - Ting Gan
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China
| | - Chengshuang Huang
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China
| | - Yanwen Duan
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China.,National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, Hunan, China.,Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, Hunan, China
| | - Xiangcheng Zhu
- Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, China.,National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, Hunan, China.,Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, Changsha, Hunan, China
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13
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Alnafakh R, Saretzki G, Midgley A, Flynn J, Kamal AM, Dobson L, Natarajan P, Stringfellow H, Martin-Hirsch P, DeCruze SB, Coupland SE, Hapangama DK. Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer. Cancers (Basel) 2021; 13:cancers13020273. [PMID: 33450922 PMCID: PMC7828388 DOI: 10.3390/cancers13020273] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 01/06/2021] [Accepted: 01/08/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Telomeres are the protective caps at the ends of chromosomes, and they are maintained by an enzyme called telomerase. Telomerase activity allows rapid reproduction of the cells (proliferation) of the lining of the womb (endometrium). Telomerase levels are high in cancers in general, including in endometrial cancer. Dyskerin is one of the main components of the telomerase enzyme. While the other main components of telomerase have been studied in endometrial cancer, there are no previous studies on dyskerin in the endometrium. Our study shows that dyskerin levels are significantly lower in endometrial cancer and levels are linked to the survival of women. Experimentally increasing dyskerin protein in endometrial cells in the laboratory reduces the rate of cell proliferation. Consequently, we propose that dyskerin may be a regulator of endometrial cancer cell proliferation, and further studies are required to test if it can be targeted to develop new therapies for endometrial cancer. Abstract Dyskerin is a core-component of the telomerase holo-enzyme, which elongates telomeres. Telomerase is involved in endometrial epithelial cell proliferation. Most endometrial cancers (ECs) have high telomerase activity; however, dyskerin expression in human healthy endometrium or in endometrial pathologies has not been investigated yet. We aimed to examine the expression, prognostic relevance, and functional role of dyskerin in human EC. Endometrial samples from a cohort of 175 women were examined with immunohistochemistry, immunoblotting, and qPCR. The EC cells were transfected with Myc-DDK-DKC1 plasmid and the effect of dyskerin overexpression on EC cell proliferation was assessed by flow cytometry. Human endometrium expresses dyskerin (DKC1) and dyskerin protein levels are significantly reduced in ECs when compared with healthy postmenopausal endometrium. Low dyskerin immunoscores were potentially associated with worse outcomes, suggesting a possible prognostic relevance. Cancer Genome Atlas (TCGA) ECs dataset (n = 589) was also interrogated. The TCGA dataset further confirmed changes in DKC1 expression in EC with prognostic significance. Transient dyskerin overexpression had a negative effect on EC cell proliferation. Our data demonstrates a role for dyskerin in normal endometrium for the first time and confirms aberrant expression with possible prognostic relevance in EC. Interventions aimed at modulating dyskerin levels may provide novel therapeutic options in EC.
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Affiliation(s)
- Rafah Alnafakh
- Liverpool Women’s Hospital NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, UK; (R.A.); (L.D.); (P.N.); (S.B.D.)
- Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK;
- Department of Pathology, Al-Hilla Teaching Hospital, Babil, Iraq
| | - Gabriele Saretzki
- Biosciences Institute, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK;
| | - Angela Midgley
- Experimental Arthritis Treatment Centre for Children, Institute in the Park, Department of Women’s and Children’s Health, University of Liverpool, Liverpool L12 2AP, UK;
| | | | - Areege M. Kamal
- Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK;
- Pathology Department, Oncology Teaching Hospital, Baghdad Medical City, Baghdad, Iraq
| | - Lucy Dobson
- Liverpool Women’s Hospital NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, UK; (R.A.); (L.D.); (P.N.); (S.B.D.)
- Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK;
| | - Purushothaman Natarajan
- Liverpool Women’s Hospital NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, UK; (R.A.); (L.D.); (P.N.); (S.B.D.)
- Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK;
| | - Helen Stringfellow
- Lancashire Teaching Hospital NHS Trust, Preston PR2 9HT, UK; (H.S.); (P.M.-H.)
| | | | - Shandya B. DeCruze
- Liverpool Women’s Hospital NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, UK; (R.A.); (L.D.); (P.N.); (S.B.D.)
| | - Sarah E. Coupland
- Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L7 8TX, UK;
| | - Dharani K. Hapangama
- Liverpool Women’s Hospital NHS Foundation Trust, Member of Liverpool Health Partners, Liverpool L8 7SS, UK; (R.A.); (L.D.); (P.N.); (S.B.D.)
- Department of Women’s and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool L8 7SS, UK;
- Correspondence:
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14
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Pańczyszyn A, Boniewska-Bernacka E, Głąb G. Telomere length in leukocytes and cervical smears of women with high-risk human papillomavirus (HR HPV) infection. Taiwan J Obstet Gynecol 2020; 59:51-55. [PMID: 32039800 DOI: 10.1016/j.tjog.2019.11.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2019] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE Persistent high-risk HPV (HR HPV) infection leads to the development of squamous intraepithelial lesions, which in turn may progress to cervical cancer. Telomere elongation or shortening may indicate a carcinogenesis process. In the present study, we analyzed telomere length from blood and cervical smears of women without and with high-risk HPV infection. MATERIALS AND METHODS Telomere length was quantified by real-time PCR in blood and cervical smears from 48 women with high-risk HPV infection and HGSIL or LGSIL, 29 women HR-HPV positive without SIL, and 11 HPV-negative women. RESULTS No correlation was found between age and telomere length in blood and cervical smears. Women with high-risk HPV infection had shorter telomeres in cervical smears, but not in blood compared to the control group. CONCLUSION These findings suggest that telomere shortening occurs in cervical cells of women with HR HPV infection both with LGSIL and HGSIL and may indicate the onset of carcinogenesis. In turn, there is no correlation between leukocyte telomere length and cervical cancer risk in women with HR HPV infection.
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Affiliation(s)
| | | | - Grzegorz Głąb
- Public Higher Medical Professional School in Opole, Poland
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15
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Arantes LMRB, Cruvinel-Carloni A, de Carvalho AC, Sorroche BP, Carvalho AL, Scapulatempo-Neto C, Reis RM. TERT Promoter Mutation C228T Increases Risk for Tumor Recurrence and Death in Head and Neck Cancer Patients. Front Oncol 2020; 10:1275. [PMID: 32850388 PMCID: PMC7399085 DOI: 10.3389/fonc.2020.01275] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 06/19/2020] [Indexed: 12/21/2022] Open
Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is usually associated to tobacco and alcohol consumption. Increased telomerase activity has been consistently detected in 80–90% of malignant tumors, including HNSCC. Mutations within the promoter region of telomerase reverse transcriptase (TERT) that confer enhanced TERT promoter activity have been reported in two major hotspots, designated C228T and C250T. Objectives: To evaluate TERT promoter mutations C228T and C250T in HNSCC patients from Brazil and correlate with patients' outcome. Materials and Methods: Formalin-fixed paraffin-embedded tissues were obtained from 88 HNSCC patients and analyzed for TERT promoter mutations C228T and C250T by pyrosequencing. Results: The overall prevalence of hotspot TERT mutations in HNSCC samples was of 27.3%, with 6.8% at locus C228T and 20.5% at C250T. The majority (92%) of mutated cases were located in oral cavity, mainly at the tongue. We observed that 94.4% of the patients harboring TERT promoter mutation C250T were alcohol consumers (p = 0.032) and 66.7% of the patients harboring TERT promoter mutation C228T were not alcohol consumers (p = 0.035). The presence of C228T mutation impacted patient outcome, with a significant decrease in disease-free survival (20.0 vs. 63.0%, p =0.017) and in overall survival (16.7 vs. 45.1%, p = 0.017). Conclusion: This is the first report of a TERT promoter mutations in HNSCC patients from South America. The high prevalence of TERT mutation, as well as its association with poor disease-free survival and overall survival, particular at C228T locus might serve as a prognostic biomarker in HNSCC to help clinicians in the management of treatment.
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Affiliation(s)
| | | | | | | | - André Lopes Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.,Department of Head and Neck Surgery, Barretos Cancer Hospital, Barretos, Brazil
| | - Cristovam Scapulatempo-Neto
- Department of Pathology, Barretos Cancer Hospital, Barretos, Brazil.,Pathology and Molecular Diagnostics Service, Diagnosticos da América-DASA, Barueri, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.,Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
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16
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Srinivasan RC, Strom SC, Gramignoli R. Effects of Cryogenic Storage on Human Amnion Epithelial Cells. Cells 2020; 9:cells9071696. [PMID: 32679793 PMCID: PMC7407665 DOI: 10.3390/cells9071696] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/17/2020] [Accepted: 07/10/2020] [Indexed: 02/07/2023] Open
Abstract
Perinatal stem cells and epithelial cells isolated from full term amnion membrane, in particular, have attracted interest over the last decade, as a promising source of multipotent cells for cellular therapies. Human amnion epithelial cells (hAEC) have been used to treat monogenetic liver disease such as maple syrup urine disease or fibrosis of the liver in preclinical studies. In most studies xeno-transplants of hAEC were conducted without providing immunosuppression to recipients, reflecting the tolerogenic properties of hAEC. For many cell types, successful cryopreservation is critical for providing a readily available, off-the-shelf product. In this study, hAEC were isolated from full-term human placenta from 14 different donors, cryopreserved using a protocol and reagents commonly adopted for epithelial cell preservation. The cells were analyzed in terms of survival, recovery, and homogeneity, profiled for surface markers characteristic of epithelial, mesenchymal, endothelial, or hematopoietic cells. There were no significant differences observed in the percentage of cells with epithelial cell markers before and after cryopreservation. The relative proportion of stromal and hematopoietic cells was significantly reduced in hAEC preparations after cryopreservation. The expression of stem cell and immunomodulatory molecules were confirmed in the final product. Since multipotent cells are readily available from full-term placenta, this novel cell source might significantly increase the number of patients eligible to receive cellular therapies for liver and other diseases.
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17
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Chen J, Morihiro K, Fukui D, Guo L, Okamoto A. Live-Cell Sensing of Telomerase Activity by Using Hybridization-Sensitive Fluorescent Oligonucleotide Probes. Chembiochem 2020; 21:1022-1027. [PMID: 31840916 DOI: 10.1002/cbic.201900555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/04/2019] [Indexed: 12/11/2022]
Abstract
Live-cell sensing of telomerase activity with simple and efficient strategies remains a challenging target. In this work, a strategy for telomerase sensing by using hybridization-sensitive fluorescent oligonucleotide probes is reported. In the presence of telomerase and dNTPs, the designed supporting strand was extended and generated the hairpin structure that catalyzed the next telomerase extending reaction. The special extension mechanism increased the local concentration of another supporting strand and telomerase, which resulted in enhanced telomerase activity. The hybridization-sensitive oligonucleotide probes bound to the hairpin catalyst and generated turn-on fluorescence. This method realized the sensing of telomerase activity in HeLa cell extract with a detection limit below 1.6×10-6 IU μL-1 . The real-time in situ observation of telomerase extension was achieved in living HeLa cells. This strategy has been applied to monitor the efficiency of telomerase-targeting anticancer drugs in situ.
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Affiliation(s)
- Jiazhuo Chen
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Kunihiko Morihiro
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Daisuke Fukui
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Lihao Guo
- Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan
| | - Akimitsu Okamoto
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.,Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan
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18
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Correlation of hTERT Expression with Cervical Cytological Abnormalities and Human Papillomavirus Infection. ACTA ACUST UNITED AC 2019; 38:143-151. [PMID: 29668478 DOI: 10.2478/prilozi-2018-0015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Telomerase Reverse Transcriptase (TERT) is the main catalytic sub-unit of telomerase, a reverse transcriptase enzyme. Telomerase expression is regulated at many levels, with numerous studies suggesting that up-regulation of human TERT gene (hTERT) at transcriptional level results in immortal cell phenotype associated with cancer. The aim of this study is to determine the correlation between hTERT expression and different cervical precursor lesions, as well as with cervical cancer in patients with confirmed Human papillomavirus (HPV) infection. The study included molecular analyzes on cervical samples from 214 women and matched Papanicolaou (Pap) test results. HPV detection and genotyping was performed by polymerase chain reaction (PCR) and genotyping. Quantitative real-time PCR (qRT-PCR) was performed using TaqMan probes and were calculated relative to the reference gene. Results showed significantly increased hTERT mRNA expression levels in high-grade and low-grade lesions compared to normal control samples (p<0.01) associated with 6.31 fold higher risk for developing ASC-US and 9.20 for LSIL. Strong correlation between HPV infection and hTERT expression in the high-grade lesions and cervical cancer was also observed. hTERT relative expression values showed 98% specificity and 100 % sensitivity as indicator of cervical lesions particularly for the ACS-H, HSIL and cervical cancer. In conclusion, hTERT expression correlate with the cytological grade of the cervical lesions and HPV infection and has a potential to be used as a diagnostic and prognostic marker.
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19
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Diagnostic and prognostic value of the detection of hTERT mRNA in renal tumors. Urol Oncol 2019; 37:749-757. [PMID: 30975552 DOI: 10.1016/j.urolonc.2019.03.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/06/2019] [Accepted: 03/13/2019] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Elevated mRNA expression of human telomerase reverse transcriptase (hTERT mRNA) is common in many types of tumors, participating in tumor growth and progression. Such expression has not been sufficiently examined in renal cancer. The goal of the present study was to quantify it and analyze its possible clinical value in the management of this pathology. PATIENTS AND METHODS The study included 111 patients who underwent surgery for renal cell carcinoma (RCC) between 2015 and 2017. Tumor samples were taken from all patients and, in 94 of them, healthy renal tissue adjacent to the tumor was also sampled. The 2 types of tissue were histologically confirmed, after which mRNA was extracted. Using real-time quantitative PCR, the expression of hTERT and glyceraldehyde-3-phosphate dehydrogenase (as endogenous control) were indirectly quantified using the crossing point (CP), which is inversely correlated with the number of sample replicates yielding positive results. These values were correlated with patient socio-demographic variables and clinical-pathological factors of the RCC. RESULTS The majority of patients were males, with an average age of 60.5 years (SD: 14.02). Most tumors (69.4%) were clear cell carcinomas. The most frequent stages were pT2 or lower (73%), while 5% were pN1 and 12% pM1. The majority of tumors (58%) were Fuhrman grades 1 or 2 (low grade). All samples of tumor and nontumor tissue expressed glyceraldehyde-3-phosphate dehydrogenase mRNA, with the CP in the tumor sample significantly lower than in the nontumor tissue (P < 0.001). The expression of hTERT mRNA was detected in 68% of tumor tissues and significantly correlated with histopathology: 100% in sarcomatoid RCC and 77.9% in clear cell carcinomas (P < 0.0001). The CP was lower in pN1 (P = 0.018), pM1 (P = 0.046), and TNM IV stages (P = 0,041). A greater number of hTERT mRNA replicas were detected in M1 patients (P = 0.0005) and TNM IV stage (P = 0.017). There was no correlation of hTERT mRNA expression with Fuhrman grade. CONCLUSIONS The quantitation of hTERT mRNA expression in RCC might be useful as a complementary diagnostic tool as well as for assessing aggressiveness of the tumor.
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Shishkin SS, Kovalev LI, Pashintseva NV, Kovaleva MA, Lisitskaya K. Heterogeneous Nuclear Ribonucleoproteins Involved in the Functioning of Telomeres in Malignant Cells. Int J Mol Sci 2019; 20:E745. [PMID: 30744200 PMCID: PMC6387250 DOI: 10.3390/ijms20030745] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/31/2019] [Accepted: 02/04/2019] [Indexed: 12/12/2022] Open
Abstract
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are structurally and functionally distinct proteins containing specific domains and motifs that enable the proteins to bind certain nucleotide sequences, particularly those found in human telomeres. In human malignant cells (HMCs), hnRNP-A1-the most studied hnRNP-is an abundant multifunctional protein that interacts with telomeric DNA and affects telomerase function. In addition, it is believed that other hnRNPs in HMCs may also be involved in the maintenance of telomere length. Accordingly, these proteins are considered possible participants in the processes associated with HMC immortalization. In our review, we discuss the results of studies on different hnRNPs that may be crucial to solving molecular oncological problems and relevant to further investigations of these proteins in HMCs.
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Affiliation(s)
- Sergey S Shishkin
- Laboratory of Biomedical Research, Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Prospekt, 33, bld. 2, 119071 Moscow, Russia.
| | - Leonid I Kovalev
- Laboratory of Biomedical Research, Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Prospekt, 33, bld. 2, 119071 Moscow, Russia.
| | - Natalya V Pashintseva
- Laboratory of Biomedical Research, Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Prospekt, 33, bld. 2, 119071 Moscow, Russia.
| | - Marina A Kovaleva
- Laboratory of Biomedical Research, Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Prospekt, 33, bld. 2, 119071 Moscow, Russia.
| | - Ksenia Lisitskaya
- Laboratory of Biomedical Research, Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Prospekt, 33, bld. 2, 119071 Moscow, Russia.
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21
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Allison DB, Sharma R, Cowan ML, VandenBussche CJ. Evaluation of Sienna Cancer Diagnostics hTERT Antibody on 500 Consecutive Urinary Tract Specimens. Acta Cytol 2018; 62:302-310. [PMID: 29874657 DOI: 10.1159/000489181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 04/12/2018] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Telomerase activity can be detected in up to 90% of urothelial carcinomas (UC). Telomerase activity can also be detected in urinary tract cytology (UTC) specimens and indicate an increased risk of UC. We evaluated the performance of a commercially available antibody that putatively binds the telomerase reverse transcriptase (hTERT) subunit on 500 UTC specimens. STUDY DESIGN Unstained CytospinTM preparations were created from residual urine specimens and were stained using the anti-hTERT antibody (SCD-A7). Two algorithms were developed for concatenating the hTERT result and cytologic diagnosis: a "no indeterminates algorithm," in which a negative cytology and positive hTERT result are considered positive, and a "high-specificity algorithm," in which a negative cytology and positive hTERT result are considered indeterminate (and thus negative for comparison to the gold standard). RESULTS The "no indeterminates algorithm" and "high-specificity algorithm" yielded a sensitivity of 60.6 and 52.1%, a specificity of 70.4 and 90.7%, a positive predictive value of 39.1 and 63.8%, and a negative predictive value of 85.0 and 85.8%, respectively. CONCLUSIONS A positive hTERT result may identify a subset of patients with an increased risk of high-grade UC (HGUC) who may otherwise not be closely followed, while a negative hTERT immunocytochemistry result is associated with a reduction in risk for HGUC.
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Affiliation(s)
- Derek B Allison
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Rajni Sharma
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Morgan L Cowan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christopher J VandenBussche
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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22
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Sultan F, Ganaie BA. Comparative oncology: Integrating human and veterinary medicine. Open Vet J 2018; 8:25-34. [PMID: 29445618 PMCID: PMC5806664 DOI: 10.4314/ovj.v8i1.5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 01/20/2018] [Indexed: 12/22/2022] Open
Abstract
Cancer constitutes the major health problem both in human and veterinary medicine. Comparative oncology as an integrative approach offers to learn more about naturally occurring cancers across different species. Canine models have many advantages as they experience spontaneous disease, have many genes similar to human genes, five to seven-fold accelerated ageing compared to humans, respond to treatments similarly as humans do and health care levels second only to humans. Also, the clinical trials in canines could generate more robust data, as their spontaneous nature mimics real-life situations and could be translated to humans.
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Affiliation(s)
- Faheem Sultan
- Indian Council of Medical Research, GADVASU-Ludhiana Punjab-141004, India
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23
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Ganesan K, Xu B. Telomerase Inhibitors from Natural Products and Their Anticancer Potential. Int J Mol Sci 2017; 19:ijms19010013. [PMID: 29267203 PMCID: PMC5795965 DOI: 10.3390/ijms19010013] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 12/10/2017] [Accepted: 12/19/2017] [Indexed: 12/25/2022] Open
Abstract
Telomeres and telomerase are nowadays exploring traits on targets for anticancer therapy. Telomerase is a unique reverse transcriptase enzyme, considered as a primary factor in almost all cancer cells, which is mainly responsible to regulate the telomere length. Hence, telomerase ensures the indefinite cell proliferation during malignancy—a hallmark of cancer—and this distinctive feature has provided telomerase as the preferred target for drug development in cancer therapy. Deactivation of telomerase and telomere destabilization by natural products provides an opening to succeed new targets for cancer therapy. This review aims to provide a fundamental knowledge for research on telomere, working regulation of telomerase and its various binding proteins to inhibit the telomere/telomerase complex. In addition, the review summarizes the inhibitors of the enzyme catalytic subunit and RNA component, natural products that target telomeres, and suppression of transcriptional and post-transcriptional levels. This extensive understanding of telomerase biology will provide indispensable information for enhancing the efficiency of rational anti-cancer drug design.
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Affiliation(s)
- Kumar Ganesan
- Food Science and Technology Program, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai 519087, China.
| | - Baojun Xu
- Food Science and Technology Program, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai 519087, China.
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24
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Zhang N, Zhang R, Zou K, Yu W, Guo W, Gao Y, Li J, Li M, Tai Y, Huang W, Song C, Deng W, Cui X. Keratin 23 promotes telomerase reverse transcriptase expression and human colorectal cancer growth. Cell Death Dis 2017; 8:e2961. [PMID: 28749462 PMCID: PMC5550880 DOI: 10.1038/cddis.2017.339] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 06/17/2017] [Accepted: 06/19/2017] [Indexed: 02/07/2023]
Abstract
The overexpression of human telomerase reverse transcriptase (hTERT) has been associated with the proliferation and migration of colorectal cancer (CRC) cells. We investigated the roles of KRT23 and hTERT in promoting CRC cell proliferation and migration. We verified the relationship between KRT23 and hTERT in CRC using streptavidin-agarose pulldown and chromatin immunoprecipitation (ChIP) assays. One hundred and fifty-four human CRC specimens were analyzed using immunohistochemistry. The roles of KRT23 and hTERT in cell growth and migration were studied using siRNA and lentiviruses in vivo and in vitro. Western blot and wound scratch analyses were used to determine the signaling pathway for KRT23-mediated activation of CRC growth and migration. Telomerase activity was measured by using the TeloTAGGG Telomerase PCR ELISA PLUS Kit. We identified KRT23 as a new hTERT promoter-binding protein. Patients with high KRT23 and hTERT expression had markedly shorter overall survival. Overexpression of KRT23 upregulated the expression of hTERT protein, hTERT promoter-driven luciferase and telomerase activity in CRC. Conversely, inhibition of KRT23 by a KRT23-specific siRNA repressed the endogenous hTERT protein, the expression of hTERT promoter-driven luciferase and telomerase activity. Overexpression of KRT23 also promoted CRC proliferation and migration. By contrast, KRT23 inhibition significantly inhibited tumor cell growth in vitro and in vivo. KRT23 promoted cancer stem cell properties and increased the expression of CD133 and CD44. These results demonstrate that KRT23 is an important cellular factor that promotes CRC growth by activating hTERT expression and that KRT23 is a potential novel therapeutic target for CRC.
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Affiliation(s)
- Ningning Zhang
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Rui Zhang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shengyang, China
| | - Kun Zou
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Wendan Yu
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Wei Guo
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Yingying Gao
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Jia Li
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Mei Li
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Yidi Tai
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Wenlin Huang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc, Guangzhou, China
| | - Chun Song
- Shanghai East Hospital, Tongji University, Shanghai, China
| | - Wuguo Deng
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiaonan Cui
- The First Affiliated Hospital and Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
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25
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Barczak W, Suchorska WM, Sobecka A, Bednarowicz K, Machczynski P, Golusinski P, Rubis B, Masternak MM, Golusinski W. hTERT C250T promoter mutation and telomere length as a molecular markers of cancer progression in patients with head and neck cancer. Mol Med Rep 2017; 16:441-446. [PMID: 28535013 DOI: 10.3892/mmr.2017.6590] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 02/27/2017] [Indexed: 12/23/2022] Open
Abstract
Squamous cell carcinoma of the head and neck (HNSCC) is the sixth leading cause of cancer worldwide, representing over half a million incidents every year. Cancer cells, including HNSCC, are characterized by increased telomerase activity. This enzymatic complex is active in ~90% of all cancer types and is responsible for the lengthening of telomeres. Highly recurrent point mutations in the human telomerase reverse transcriptase (hTERT) promoter have recently been reported in a number of human neoplasms. The aim of the present study was to analyze the prevalence of the hTERT promoter C250T mutation and telomere length in the blood leukocytes of 61 patients with HNSCC and 49 healthy individuals. Quantitative polymerase chain reaction identified the hTERT promoter mutation in 36% of patients with HNSCC. To the best of our knowledge this is first report indicating the presence of shorter telomeres in early stage tumors. In addition, the results suggest that the C250T hTERT promoter mutation and telomere length assessment may serve as important molecular markers of HNSCC progression.
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Affiliation(s)
- Wojciech Barczak
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Garbary, Poznan, Greater Poland Voivodeship 61‑866, Poland
| | - Wiktoria M Suchorska
- Radiobiology Lab, The Greater Poland Cancer Centre, Garbary, Poznan, Greater Poland Voivodeship 61‑866, Poland
| | - Agnieszka Sobecka
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Garbary, Poznan, Greater Poland Voivodeship 61‑866, Poland
| | - Karolina Bednarowicz
- Radiobiology Lab, The Greater Poland Cancer Centre, Garbary, Poznan, Greater Poland Voivodeship 61‑866, Poland
| | - Piotr Machczynski
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Garbary, Poznan, Greater Poland Voivodeship 61‑866, Poland
| | - Pawel Golusinski
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Garbary, Poznan, Greater Poland Voivodeship 61‑866, Poland
| | - Blazej Rubis
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Przybyszewskiego, Poznan, Greater Poland Voivodeship 60‑355, Poland
| | - Michal M Masternak
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Garbary, Poznan, Greater Poland Voivodeship 61‑866, Poland
| | - Wojciech Golusinski
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Garbary, Poznan, Greater Poland Voivodeship 61‑866, Poland
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26
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Pal D, Singh SK, Kakkar N, Prasad R. Expression of Telomere Binding Proteins (RAP1 and POT1) in Renal Cell Carcinoma and Their Correlation with Clinicopathological Parameters. Indian J Clin Biochem 2017; 32:301-305. [PMID: 28811689 PMCID: PMC5539006 DOI: 10.1007/s12291-016-0611-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 08/18/2016] [Indexed: 01/20/2023]
Abstract
Telomere stability is indispensable for continuous proliferation of cells. Telomere structure is maintained by group of six proteins termed as shelterin. RAP1 and POT1 proteins are significant members of shelterin complex. Expression of RAP1 and POT1 are crucial for telomere maintenance and hence uncontrolled division of cells. Notably, expression of RAP1 and POT1 is unknown in renal cell carcinoma (RCC). In view of these facts, the present study was initiated to investigate the expression of RAP1 and POT1 in RCC and their relationships with clinicopathological features. In total 65 histopathologically confirmed RCC cases and their adjacent normal renal parenchyma were analyzed for gene expression. The mRNA expression of telomere binding proteins RAP1 and POT1 were measured using RT-PCR. Expression of RAP1 was observed to be significantly increased in tumour tissues as compared to corresponding normal renal tissues (P = 0.004). The gene expression of RAP1 was documented to be related to grades of RCC (P = 0.002) and subtypes of RCC (P = 0.01). Although, POT1 expression was up-regulated in RCC tissue, however it was not statistically significant. Also, POT1 expression was not related to grades, stages and subtypes of RCC. This is the first study which shows correlation RAP1 with grades and subtypes of RCC.
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Affiliation(s)
- Deeksha Pal
- Department of Biochemistry, PGIMER, Chandigarh, India
- Department of Urology, University of Louisville, Louisville, KY USA
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27
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Huang WJ, Li M, Jin XH, Huang XJ, Zhao W, Tian XP. Genetic profile and biological implication of PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) in human cancers: an analysis using The Cancer Genome Atlas. Oncotarget 2017; 8:67241-67253. [PMID: 28978030 PMCID: PMC5620170 DOI: 10.18632/oncotarget.18589] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 05/03/2017] [Indexed: 12/15/2022] Open
Abstract
Pin2/TRF1-interacting telomere inhibitor 1 (PinX1) was originally identified as a telomerase inhibitor, involved in maintaining telomerase activity, telomere length, and chromosomal stability. However, research has shown that PinX1 can have opposing molecular status in its expression patterns in several other tumor types. We thus investigated the genetic profile and biological implication of PinX1 in several human cancers using the cBioportal database. Our results showed that PinX1 deletion accounted for the most alterations, with the frequency of its deletion regularly occurring in pathological types of carcinosarcoma and adenocarcinoma. We found few instances of PinX1 gene mutations and 3D structural analysis demonstrated that these mutation sites were always located within telomerase inhibitor domains. Furthermore, our analysis of several human cancers from the cBioportal database revealed more frequent PinX1 homozygous depletion and PinX1 heterozygous deficiency, but both more infrequent PinX1 gain and rare instances of PinX1 amplification. The status of PinX1 genetic alterations was correlated with prognosis and may be tumor-type specific. As such, its biological function in tumorigenesis and later prognosis is complicated and may involve co-worked with NEIL2, R3HCC1, POLR3D, GTF2E2, and INTS10. In addition, we observed that PinX1 interacts with TERT, DKC1, PTGES3, and HSP90AA1. PinX1 mRNA expression was decreased in most selected cancer tissues, which could promote tumor growth and enhance tumorigenicity. Collectively, our data reveal PinX1 expression patterns and potential mechanisms in various human cancers. Further work will be needed to comprehensively examine its role in tumor genesis and progression.
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Affiliation(s)
- Wei-Juan Huang
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Department of Pharmacology, Jinan University, Guangzhou, China
| | - Mei Li
- Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Han Jin
- The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiao-Jia Huang
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Wei Zhao
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Peng Tian
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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28
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Liu X, Wang Y, Chang G, Wang F, Wang F, Geng X. Alternative Splicing of hTERT Pre-mRNA: A Potential Strategy for the Regulation of Telomerase Activity. Int J Mol Sci 2017; 18:ijms18030567. [PMID: 28272339 PMCID: PMC5372583 DOI: 10.3390/ijms18030567] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/14/2017] [Accepted: 03/02/2017] [Indexed: 12/11/2022] Open
Abstract
The activation of telomerase is one of the key events in the malignant transition of cells, and the expression of human telomerase reverse transcriptase (hTERT) is indispensable in the process of activating telomerase. The pre-mRNA alternative splicing of hTERT at the post-transcriptional level is one of the mechanisms for the regulation of telomerase activity. Shifts in splicing patterns occur in the development, tumorigenesis, and response to diverse stimuli in a tissue-specific and cell type–specific manner. Despite the regulation of telomerase activity, the alternative splicing of hTERT pre-mRNA may play a role in other cellular functions. Modulating the mode of hTERT pre-mRNA splicing is providing a new precept of therapy for cancer and aging-related diseases. This review focuses on the patterns of hTERT pre-mRNA alternative splicing and their biological functions, describes the potential association between the alternative splicing of hTERT pre-mRNA and telomerase activity, and discusses the possible significance of the alternative splicing of the hTERT pre-mRNA in the diagnosis, therapy, and prognosis of cancer and aging-related diseases.
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Affiliation(s)
- Xuewen Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin 300070, China.
| | - Yuchuan Wang
- Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin 300070, China.
- Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 300070, China.
| | - Guangming Chang
- Department of Clinical Laboratory, General Hospital, Tianjin Medical University, Tianjin 300070, China.
| | - Feng Wang
- Department of Genetics, Tianjin Medical University, Tianjin 300070, China.
| | - Fei Wang
- Department of Neurology, General Hospital, Tianjin Medical University, Tianjin 300052, China.
| | - Xin Geng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin 300070, China.
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29
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Kumar A, Nilednu P, Kumar A, Sharma NK. Epigenetic perturbation driving asleep telomerase reverse transcriptase: Possible therapeutic avenues in carcinoma. Tumour Biol 2017; 39:1010428317695951. [PMID: 28347254 DOI: 10.1177/1010428317695951] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025] Open
Abstract
In the last decade, implications of human telomerase reverse transcriptase (hTERT), a component of ribonucleoprotein telomerase in aging, senescence, and stem cell are highly evident. Besides, the activation of hTERT is also being documented several cancer types including carcinoma. The awakening of telomerase during carcinoma initiation and development is being seen with different perspectives including genetic and epigenetic tools and events. In view of several tumor progenitors genes (also referred as epigenetic mediators), telomerase is placed as key enzyme to achieve the carcinoma phenotype and sustain during the progression. It is true that swaying of telomerase in carcinoma could be facilitated with dedicated set of epigenetic modulators and modifiers players. These epigenetic alterations are heritable, potentially reversible, and seen as the epigenetic signature of carcinoma. Several papers converge to suggest that DNA methylation, histone modification, and small non-coding RNAs are the widely appreciated epigenetic changes towards hTERT modulation. In this review, we summarize the contribution of epigenetic factors in the telomerase activation and discuss potential avenues to achieve therapeutic intervention in carcinoma.
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Affiliation(s)
- Ajay Kumar
- Cancer and Translational Research Lab, Department of Biotechnology, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Pune, India
| | - Pritish Nilednu
- Cancer and Translational Research Lab, Department of Biotechnology, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Pune, India
| | - Azad Kumar
- Cancer and Translational Research Lab, Department of Biotechnology, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Pune, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Department of Biotechnology, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Pune, India
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30
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Ennour-Idrissi K, Maunsell E, Diorio C. Telomere Length and Breast Cancer Prognosis: A Systematic Review. Cancer Epidemiol Biomarkers Prev 2016; 26:3-10. [PMID: 27677729 DOI: 10.1158/1055-9965.epi-16-0343] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 08/26/2016] [Accepted: 09/16/2016] [Indexed: 01/12/2023] Open
Abstract
Telomeres ensure genome integrity during replication. Loss of telomeric function leads to cell immortalization and accumulation of genetic alterations. The association of telomere length (TL) with breast cancer prognosis is examined through a systematic review. Electronic databases (MEDLINE, EMBASE, CENTRAL), from inception to December 2015, and relevant reviews were searched. Studies that evaluated TL (blood and/or tumor) in association with breast cancer survival or prognostic factor were included. Thirty-six studies met inclusion criteria. Overall risk of bias was critical. Eight studies reported survival outcomes. Overall, there was a trend toward an association of longer telomeres with better outcomes (tumor, not blood). Of the 33 studies reporting associations with prognostic factors, nine adjusted for potential confounders. Among the latter, shorter telomeres were associated with older age (blood, not tumor), higher local recurrence rates (normal tissue), higher tumor grade (tumor), and lower physical activity (blood), which were reported in one study each. TL was not associated with molecular subtype (blood, one study), family history (tumor, one study), chemotherapy (blood, three of four studies), and stress reduction interventions (blood, two of two studies). Although major methodologic differences preclude from drawing conclusive results, TL could be a valuable breast cancer prognostic marker. Cancer Epidemiol Biomarkers Prev; 26(1); 3-10. ©2016 AACR.
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Affiliation(s)
- Kaoutar Ennour-Idrissi
- Axe Oncologie, Centre de Recherche du CHU de Québec-Université Laval, Québec, Canada.,Centre de Recherche sur le Cancer, Université Laval, Québec, Canada.,Département de Médecine Sociale et Préventive, Faculté de Médecine, Université Laval, Québec, Canada
| | - Elizabeth Maunsell
- Axe Oncologie, Centre de Recherche du CHU de Québec-Université Laval, Québec, Canada.,Centre de Recherche sur le Cancer, Université Laval, Québec, Canada.,Département de Médecine Sociale et Préventive, Faculté de Médecine, Université Laval, Québec, Canada.,Centre des Maladies du Sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Québec, Canada
| | - Caroline Diorio
- Axe Oncologie, Centre de Recherche du CHU de Québec-Université Laval, Québec, Canada. .,Centre de Recherche sur le Cancer, Université Laval, Québec, Canada.,Département de Médecine Sociale et Préventive, Faculté de Médecine, Université Laval, Québec, Canada.,Centre des Maladies du Sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Québec, Canada
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31
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La SH, Kim SJ, Kang HG, Lee HW, Chun KH. Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism. Oncotarget 2016; 7:57117-57130. [PMID: 27494887 PMCID: PMC5302977 DOI: 10.18632/oncotarget.10986] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 07/19/2016] [Indexed: 12/20/2022] Open
Abstract
The human Telomerase Reverse Transcriptase (hTERT) gene encodes a rate-limiting catalytic subunit of telomerase that maintains genomic integrity. Suppression of hTERT expression could induce cellular senescence and is considered a potent approach for gastric cancer therapy. However, control of hTERT expression and function remains poorly understood in gastric cancer. In this study, we demonstrated that high expression levels of hTERT in malignant tissues are correlated with poor survival probability in gastric cancer patients. Knockdown of hTERT expression retarded cell proliferation and cellular senescence, which was confirmed by increased protein expression levels of p21cip1 and p27kip1, and decreased phosphorylation of Rb. In contrast, overexpression of hTERT increased cell proliferation and decreased cellular senescence. Remarkably, the down-regulation of hTERT expression was detected in lgals3-/- mouse embryo fibroblasts (MEFs). Knockdown of galectin-3 decreased the expression of hTERT in gastric cancer cells. Galectin-3 ablation-induced cellular senescence was rescued by concomitant overexpression of hTERT. hTERT ablation-induced cellular senescence and p21cip1 and p27kip1 expression was rescued by concomitant overexpression of galectin-3. The size of tumor burdens was increased in hTERT-overexpressed gastric cancer cells xenografted mice, whereas it was repressed by concomitant depletion of galectin-3. Additionally, we determined that the N-terminal domain of galectin-3 directly interacted with hTERT. The telomeric activity of hTERT was also decreased by galectin-3 ablation. Taken together, ablation of hTERT induces cellular senescence and inhibits the growth of gastric cancer cells, suggesting that it could be a potent target in gastric cancer therapy. We also propose that galectin-3 is an important regulator of hTERT expression and telomeric activity in gastric tumorigenesis.
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Affiliation(s)
- Sun-Hyuk La
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Seok-Jun Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Hyeok-Gu Kang
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Han-Woong Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Kyung-Hee Chun
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea
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32
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Plumbagin triggers DNA damage response, telomere dysfunction and genome instability of human breast cancer cells. Biomed Pharmacother 2016; 82:256-68. [DOI: 10.1016/j.biopha.2016.05.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 05/04/2016] [Accepted: 05/04/2016] [Indexed: 12/21/2022] Open
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33
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Strom SC, Gramignoli R. Human amnion epithelial cells expressing HLA-G as novel cell-based treatment for liver disease. Hum Immunol 2016; 77:734-9. [PMID: 27476049 DOI: 10.1016/j.humimm.2016.07.002] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 06/20/2016] [Accepted: 07/01/2016] [Indexed: 02/06/2023]
Abstract
Despite routine liver transplantation and supporting medical therapies, thousands of patients currently wait for an organ and there is an unmet need for more refined and widely available regenerative strategies to treat liver diseases. Cell transplants attempt to maximize the potential for repair and/or regeneration in liver and other organs. Over 40years of laboratory pre-clinical research and 25years of clinical procedures have shown that certain liver diseases can be treated by the infusion of isolated cells (hepatocyte transplant). However, like organ transplants, hepatocyte transplant suffers from a paucity of tissues useful for cell production. Alternative sources have been investigated, yet with limited success. The tumorigenic potential of pluripotent stem cells together with their primitive level of hepatic differentiation, have limited the use of stem cell populations. Stem cell sources from human placenta, and the amnion tissue in particular are receiving renewed interest in the field of regenerative medicine. Unlike pluripotent stem cells, human amnion epithelial (AE) cells are easily available without ethical or religious concerns; they do not express telomerase and are not immortal or tumorigenic when transplanted. In addition, AE cells have been reported to express genes normally expressed in mature liver, when transplanted into the liver. Moreover, because of the possibility of an immune-privileged status related to their expression of HLA-G, it might be possible to transplant human AE cells without immunosuppression of the recipient.
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Affiliation(s)
- Stephen C Strom
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
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Telomerase activity in non-small cell lung cancer. POLISH JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 2016; 13:15-20. [PMID: 27212973 PMCID: PMC4860429 DOI: 10.5114/kitp.2016.58959] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 10/25/2015] [Accepted: 12/31/2015] [Indexed: 11/17/2022]
Abstract
INTRODUCTION High telomerase activity has been detected in the majority of malignant neoplasms including lung cancer. The purpose of the study was to attempt to use telomerase activity as a prognostic factor in patients with non-small cell lung cancer (NSCLC). MATERIAL AND METHODS Telomerase activity was analyzed in 47 tissue specimens taken from patients with NSCLC. The control group consisted of 30 specimens of non-cancerous lung parenchyma. Telomerase activity was measured by means of the telomeric repeat amplification protocol (TRAP). RESULTS Telomerase activity in the neoplastic tissue was significantly higher than in the lung parenchyma that was free from neoplastic infiltration. There was no significant association between telomerase activity and age, gender, tobacco smoking, histological type of the tumor, or staging (pTNM). No association was found between the level of telomerase activity in NSCLC specimens and the two-year survival rate of patients (p = 0.326). A higher level of telomerase activity in poorly differentiated tumors (G3) as compared to moderately differentiated tumors (G2) was detected (p = 0.008). A positive association was identified between telomerase activity in pulmonary parenchyma free from tumor infiltration and the presence of leukocyte infiltration (p = 0.0001). CONCLUSIONS No association was found between the level of telomerase activity in NSCLC specimens and the two-year survival rate of patients. The study has revealed a positive association between telomerase activity and the grade of differentiation (G) in NSCLC.
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Ceja-Rangel HA, Sánchez-Suárez P, Castellanos-Juárez E, Peñaroja-Flores R, Arenas-Aranda DJ, Gariglio P, Benítez-Bribiesca L. Shorter telomeres and high telomerase activity correlate with a highly aggressive phenotype in breast cancer cell lines. Tumour Biol 2016; 37:11917-11926. [PMID: 27072825 DOI: 10.1007/s13277-016-5045-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 04/01/2016] [Indexed: 12/12/2022] Open
Abstract
Maintenance of telomere length is one function of human telomerase that is crucial for the survival of cancer cells and cancer progression. Both telomeres and telomerase have been proposed as possible biomarkers of cancer risk and cancer invasiveness; however, their clinical relevance is still under discussion. In order to improve our understanding of the relationship between telomere length and telomerase activity with cancer invasiveness, we studied telomere length as well as telomerase levels, activity, and intracellular localization in breast cancer cell lines with diverse invasive phenotypes. We found an apparently paradoxical coincidence of short telomeres and enhanced telomerase activity in the most invasive breast cancer cell lines. We also observed that hTERT intracellular localization could be correlated with its level of activity. There was no association between human telomerase reverse transcriptase (hTERT) protein expression levels and invasiveness. We propose that simultaneous evaluation of these two biomarkers-telomere length and telomerase activity-could be useful for the assessment of the invasive capacity and aggressiveness of tumor cells from breast cancer patients.
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Affiliation(s)
- Hugo A Ceja-Rangel
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Av. Instituto Politécnico Nacional 2508, 07360, Ciudad de México, Mexico.,Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico
| | - Patricia Sánchez-Suárez
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico
| | - Emilio Castellanos-Juárez
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico
| | - Rubicelia Peñaroja-Flores
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico
| | - Diego J Arenas-Aranda
- Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Ciudad de México, Mexico
| | - Patricio Gariglio
- Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Av. Instituto Politécnico Nacional 2508, 07360, Ciudad de México, Mexico.
| | - Luis Benítez-Bribiesca
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, 06725, Ciudad de México, Mexico.
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Xie XC, Ge LY, Lai H, Qiu H, Tang F, Qin YZ. The Relationship between Telomerase Activity and Clinicopathological Parameters in Colorectal Cancer: A Meta-Analysis. Balkan Med J 2016; 33:64-71. [PMID: 26966620 DOI: 10.5152/balkanmedj.2015.151182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 05/19/2015] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Recently, accumulated research has found that the expression of telomerase activity (TA) was associated with colorectal cancer (CRC) advancement, whereas the TA prognostic effect in CRC patients is still controversial. AIMS To investigate relationships between TA and CRC clinicopathological parameters. STUDY DESIGN Meta-analysis study. METHODS We searched published studies in databases, such as EMBASE, the Cochrane Library, PubMed, and Ovid databases (last search updated to October 2014) by meeting specified search criteria. The quality of the included studies was usually evaluated and a meta-analysis was implemented by Stata 12.0 software. We used an odds ratio (OR) with a 95% confidence interval (CI) to evaluate relationship strengths between TA and CRC clinicopathological parameters. RESULTS In total, 11 studies (715 patients) were included to assess the relation between TA and metastasis-related parameters in CRC patients. The results indicate that a senior TA expression was connected with the existence of lymph node metastasis (180 patients; OR=2.85, 95% CI=1.40-5.81, p=0.004), and tumor site (522 patients; OR=2.93, 95% CI=1.29-6.67, p=0.010). However, a senior TA expression was not connected with tumor size (137 patients; OR=1.57, 95% CI=0.71-3.47, p=0.267), histological differentiation (570 patients; OR=1.28, 95% CI=0.78-2.09, p=0.332), depth of invasion (57 patients; OR=3.76, 95% CI=0.61-23.04, p=0.152), distant metastasis (123 patients; OR=1.76, 95% CI=0.54-5.74, p=0.346), and clinical stage of the cancer (543 patients; OR=1.59, 95% CI=0.74-3.38, p=0.232). CONCLUSION This meta-analysis suggests that a positive TA was correlated with lymph node metastasis progression and tumor site of the CRC but did not correlate with other important clinicopathological parameters. TA can play a useful part in the prognosis and treatment of CRC patients, but further studies are required to confirm this.
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Affiliation(s)
- Xue-Cheng Xie
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Lian-Ying Ge
- Department of Endoscopy Center, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Hao Lai
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Hai Qiu
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Fan Tang
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Yu-Zhou Qin
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
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37
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Telomere Length Maintenance and Cardio-Metabolic Disease Prevention Through Exercise Training. Sports Med 2016; 46:1213-37. [DOI: 10.1007/s40279-016-0482-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Barczak W, Rozwadowska N, Romaniuk A, Lipińska N, Lisiak N, Grodecka-Gazdecka S, Książek K, Rubiś B. Telomere length assessment in leukocytes presents potential diagnostic value in patients with breast cancer. Oncol Lett 2016; 11:2305-2309. [PMID: 26998167 DOI: 10.3892/ol.2016.4188] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 01/05/2016] [Indexed: 11/05/2022] Open
Abstract
Telomere shortening is associated with cancer development, primarily through the induction of genomic instability. The majority of studies have indicated that individuals with shorter blood telomeres may be at a higher risk of developing various types of cancer. There is increasing evidence that the study of the alterations in telomere length may improve cancer prognosis. The aim of the present study was to verify the use of telomere length parameters in the diagnostics of breast cancer stage. Telomere length was analyzed in the blood leukocytes of 52 patients with breast cancer relative to 47 control subjects using quantitative polymerase chain reaction. The effects of stage, grade, estrogen receptor, progesterone receptor and human epidermal growth factor 2 (HER2) status were assessed. The current study demonstrated that the average telomeric sequence length was significantly shorter in leukocytes from individuals diagnosed with a more severe stage of breast cancer (T2N1M0) than in leukocytes in the early stages of the disease (T1N0M0) (P=0.0207). Furthermore, the data indicated that telomeres in leukocytes derived from patients with HER2+ breast cancer were significantly longer compared with those with the HER2- type (P=0.0347). These results suggest that the assessment of telomeres in blood leukocytes may, at least partially, correspond with breast cancer staging and HER2 receptor status.
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Affiliation(s)
- Wojciech Barczak
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, The Greater Poland Cancer Centre, Poznan 61-866, Poland; Radiobiology Laboratory, Department of Medical Physics, The Greater Poland Cancer Centre, Poznan 61-866, Poland
| | - Natalia Rozwadowska
- Institute of Human Genetics, Polish Academy of Sciences, Poznan 60-479, Poland
| | - Aleksandra Romaniuk
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Natalia Lipińska
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Natalia Lisiak
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | | | - Krzysztof Książek
- Department of Pathophysiology, Laboratory of Gerontology, Poznan University of Medical Sciences, Poznan 60-781, Poland
| | - Błażej Rubiś
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Poznan 60-355, Poland
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Hakobyan A, Nersisyan L, Arakelyan A. Quantitative trait association study for mean telomere length in the South Asian genomes. Bioinformatics 2016; 32:1697-700. [PMID: 26803156 DOI: 10.1093/bioinformatics/btw027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 01/13/2016] [Indexed: 01/26/2023] Open
Abstract
MOTIVATION Mean telomere length (MTL) is associated with cancers and age-related diseases, which necessitates identification of genomic and environmental factors that impact telomere length dynamics. Here, we present a pilot genome wide association (GWA) study for MTL in South Asian population using publicly available next generation whole genome sequences (WGS), both for MTL and genotype calculations. RESULTS MTL in the studied population was not correlated with age, which is in accordance with previous reports. Further, we identified that individuals with Sikh religion had longer telomeres, which may be the result of complex interaction between genetic background and environmental factors. Finally, we identified 51 MTL-associated SNPs residing in five loci. The top ones were located in ADARB2 gene, which has previously been implicated with extreme old age. CONCLUSION Our results show that WGS data can be used in telomere length studies. In addition, we introduce novel loci implicated in MTL that may be worth considering in further telomere studies. CONTACT aarakelyan@sci.am SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Anna Hakobyan
- Bioinformatics Group, Institute of Molecular Biology NAS RA, Yerevan 0014, Armenia, College of Science and Engineering, American University of Armenia, Yerevan 0019, Armenia and
| | - Lilit Nersisyan
- Bioinformatics Group, Institute of Molecular Biology NAS RA, Yerevan 0014, Armenia, Synopsys Inc., Yerevan 0026, Armenia
| | - Arsen Arakelyan
- Bioinformatics Group, Institute of Molecular Biology NAS RA, Yerevan 0014, Armenia, Synopsys Inc., Yerevan 0026, Armenia
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40
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Wu Y, Li G, He D, Yang F, He G, He L, Zhang H, Deng Y, Fan M, Shen L, Zhou D, Zhang Z. Telomerase reverse transcriptase methylation predicts lymph node metastasis and prognosis in patients with gastric cancer. Onco Targets Ther 2016; 9:279-86. [PMID: 26834487 PMCID: PMC4716758 DOI: 10.2147/ott.s97899] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Purpose Telomerase activity is associated with cellular immortalization and is present in most human tumors but absent in normal tissues. The activity of telomerase reverse transcriptase (TERT), a catalytic telomerase subunit, correlates with telomerase activity in tumors. The objective of this study was to investigate TERT promoter methylation and its prognostic impact in gastric cancer (GC). Patients and methods The analysis of TERT promoter methylation was performed in tumors and corresponding normal tissues of 116 patients with GC using a highly sensitive Sequenom Epityper assay. The expression of TERT in GC tissues was measured by quantitative real-time polymerase chain reaction. Results The levels of TERT promoter methylation in GC samples were significantly higher than in normal adjacent tissues (P=0.002). Hypermethylation of TERT promoter was associated with high T-stage (P=0.024), late N-stage (P=0.006), and lymphovascular/neural invasion (P=0.035), without correlation with age, sex, or histological grade. Simple linear regression analysis showed that TERT mRNA correlated positively with TERT methylation (R2=0.562, P=0.001). Also, higher TERT mRNA expression was related to hypermethylation of TERT promoter in GC samples (P=0.005). Univariate analysis demonstrated that N-stage (P=0.002) and TERT promoter methylation (P=0.004) were predictive of overall survival. Furthermore, multivariate analysis confirmed that N-stage (P=0.013) and TERT promoter methylation (P=0.031) were independent prognostic indicators for overall survival. Conclusion Our data suggested that hypermethylation of TERT promoter may contribute to gastric wall invasion, lymph node metastasis, lymphovascular/neural invasion, and poor prognosis in GC. GC patients with hypermethylation of TERT promoter could be eligible for close follow-up.
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Affiliation(s)
- Yongxin Wu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Guichao Li
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Dong He
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Fengping Yang
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Guang He
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Lin He
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Yun Deng
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Ming Fan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Daizhan Zhou
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
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Carkic J, Nikolic N, Radojevic-Skodric S, Kuzmanovic-Pficer J, Brajovic G, Antunovic M, Milasin J, Popovic B. The role of TERT-CLPTM1L SNPs, hTERT expression and telomere length in the pathogenesis of oral squamous cell carcinoma. J Oral Sci 2016; 58:449-458. [DOI: 10.2334/josnusd.16-0108] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Affiliation(s)
- Jelena Carkic
- Institute of Human Genetics, School of Dental Medicine, University of Belgrade
| | - Nadja Nikolic
- Institute of Human Genetics, School of Dental Medicine, University of Belgrade
| | | | - Jovana Kuzmanovic-Pficer
- Department for Medical Statistics and Informatics, School of Dental Medicine, University of Belgrade
| | - Gavrilo Brajovic
- Department of Physiology, School of Dental Medicine, University of Belgrade
| | - Marija Antunovic
- Clinic of Oral Surgery, School of Medicine, University of Montenegro
| | - Jelena Milasin
- Institute of Human Genetics, School of Dental Medicine, University of Belgrade
| | - Branka Popovic
- Institute of Human Genetics, School of Dental Medicine, University of Belgrade
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Mosrati MA, Willander K, Falk IJ, Hermanson M, Höglund M, Stockelberg D, Wei Y, Lotfi K, Söderkvist P. Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis. Oncotarget 2015; 6:25109-20. [PMID: 26298771 PMCID: PMC4694818 DOI: 10.18632/oncotarget.4668] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 07/10/2015] [Indexed: 12/17/2022] Open
Abstract
Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where also overall survival was assessed. A significant association for increased risk of AML was found for TERT SNVs, rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, higher age and treatment. No hot spot TERT promoter mutations at -228C > T or -250C > T or POT1 mutations could be identified in this AML cohort. We show that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify high risk normal karyotype-AML (NK-AML) patients, for treatment guidance.
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MESH Headings
- Adolescent
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Case-Control Studies
- DNA Mutational Analysis
- Female
- Gene Frequency
- Genetic Association Studies
- Genetic Predisposition to Disease
- Heterozygote
- Homozygote
- Humans
- Kaplan-Meier Estimate
- Karyotyping
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/enzymology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/therapy
- Male
- Middle Aged
- Multivariate Analysis
- Mutation
- Odds Ratio
- Phenotype
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Proportional Hazards Models
- Risk Factors
- Telomerase/genetics
- Time Factors
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Mohamed Ali Mosrati
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Kerstin Willander
- Department of Haematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Ingrid Jakobsen Falk
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Monica Hermanson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Martin Höglund
- Division of Hematology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Dick Stockelberg
- Section for Hematology and Coagulation, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Yuan Wei
- Section for Hematology and Coagulation, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Kourosh Lotfi
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
- Department of Hematology, County Council of Östergötland, Linköping, Sweden
| | - Peter Söderkvist
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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Pal D, Sharma U, Khajuria R, Singh SK, Kakkar N, Prasad R. Augmented telomerase activity, reduced telomere length and the presence of alternative lengthening of telomere in renal cell carcinoma: plausible predictive and diagnostic markers. Gene 2015; 562:145-151. [PMID: 25769384 DOI: 10.1016/j.gene.2015.02.079] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 02/04/2015] [Accepted: 02/12/2015] [Indexed: 12/11/2022]
Abstract
In this study, we analyzed 100 cases of renal cell carcinoma (RCC) for telomerase activity, telomere length and alternative lengthening of telomeres (ALT) using the TRAP assay, TeloTTAGGG assay kit and immunohistochemical analysis of ALT associated promyelocytic leukemia (PML) bodies respectively. A significantly higher (P=0.000) telomerase activity was observed in 81 cases of RCC which was correlated with clinicopathological features of tumor for instance, stage (P=0.008) and grades (P=0.000) but not with the subtypes of RCC (P = 0.355). Notwithstanding, no correlation was found between telomerase activity and subtypes of RCC. Strikingly, the telomere length was found to be significantly shorter in RCC (P=0.000) to that of corresponding normal renal tissues and it is well correlated with grades (P=0.016) but not with stages (P=0.202) and subtypes (P=0.669) of RCC. In this study, telomere length was also negatively correlated with the age of patients (r(2)=0.528; P=0.000) which supports the notion that it could be used as a marker for biological aging. ALT associated PML bodies containing PML protein was found in telomerase negative cases of RCC. It suggests the presence of an ALT pathway mechanism to maintain the telomere length in telomerase negative RCC tissues which was associated with high stages of RCC, suggesting a prevalent mechanism for telomere maintenance in high stages. In conclusion, the telomerase activity and telomere length can be used as a diagnostic as well as a predictive marker in RCC. The prevalence of ALT mechanism in high stages of RCC is warranted for the development of anti-ALT inhibitors along with telomerase inhibitor against RCC as a therapeutic approach.
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Affiliation(s)
- Deeksha Pal
- Department of Biochemistry, PGIMER, Chandigarh, India
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Zhao H, Li Y, Wang S, Yang Y, Wang J, Ruan X, Yang Y, Cai K, Zhang B, Cui P, Yan J, Zhao Y, Wakeland EK, Li Q, Hu S, Fang X. Whole transcriptome RNA-seq analysis: tumorigenesis and metastasis of melanoma. Gene 2014; 548:234-43. [PMID: 25034661 DOI: 10.1016/j.gene.2014.07.038] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 06/27/2014] [Accepted: 07/12/2014] [Indexed: 12/31/2022]
Abstract
Melanoma is the most malignant cutaneous cancer and causes over 9000 deaths annually. Because fatality rates from malignant melanoma (MM) increase dramatically upon metastasis, we investigated tumorigenesis and metastasis of MM in transcriptome analyses of three distinct cell lines that correspond with the stages of MM pathogenesis: the normal stage (HEMn-LP), the onset of MM (A375), and the metastasis stage (A2058). Using next-generation sequencing (NGS) technology, we detected asymmetrical expression of genes among the three cell lines, notably on chromosomes 9, 11, 12, and 14, suggesting their involvement in tumorigenesis and metastasis of MM. These genes were clustered into 41 categories based on their expression patterns, and their biological functions were analyzed using Ingenuity Pathway Analysis. In the top cancer-associated category, HIF1A, IL8, TERT, ONECUT1, and FOXA1 directly interacted with either transcription factors or cytokines that are known to be involved in the tumorigenesis or metastasis of other malignant tumors. The present data suggest that cytokine regulatory pathways in macrophages predominate over other pathways during the pathogenesis of MM. This study provides new targets for the downstream mechanistic studies of the tumorigenesis and metastasis of MM and demonstrates a new strategy for studies of the progression of other malignant cancers.
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Affiliation(s)
- Hua Zhao
- Department of Dermatology, General Hospital of People's Liberation Army, Beijing 100853, China
| | - Yongjun Li
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Shaobin Wang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yadong Yang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Junyun Wang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiuyan Ruan
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yaran Yang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Kan Cai
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Bing Zhang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Peng Cui
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Jiangwei Yan
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yongliang Zhao
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Edward K Wakeland
- Department of Immunology & Microarray Core Facility, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Quanzhen Li
- Department of Immunology & Microarray Core Facility, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Songnian Hu
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
| | - Xiangdong Fang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
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Ayiomamitis GD, Notas G, Zaravinos A, Drygiannakis I, Georgiadou M, Sfakianaki O, Mastrodimou N, Thermos K, Kouroumalis E. Effects of octreotide and insulin on colon cancer cellular proliferation and correlation with hTERT activity. Oncoscience 2014; 1:457-67. [PMID: 25594044 PMCID: PMC4284627 DOI: 10.18632/oncoscience.58] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Accepted: 06/28/2014] [Indexed: 12/15/2022] Open
Abstract
Peptide hormone somatostatin and its receptors have a wide range of physiological functions and play a role in the treatment of numerous human diseases, including colorectal cancer. Octreotide, a synthetic somatostatin-analog peptide, inhibits growth of colonic cancer cells primarily by binding to G-protein coupled receptors and elicits cellular responses through second-messenger systems. Insulin also initiates mitogenic signals in certain cell types. The objective of the present study was to explore the effects of octreotide with or without insulin treatment, on Caco-2 and HT-29 human colon-cancer cell proliferation and to correlate their effects with the activation of telomerase reverse transcriptase (hTERT). The involvement of protein tyrosine phosphatases in the regulation of the anti-proliferative effect of octreotide was also evaluated. Sodium orthovanadate was used to reverse the anti- proliferative effect of octreotide. Telomerase activity was determined for each time point under octreotide and/or insulin treatment. Elevated expression of sst1, sst2 and sst5 was confirmed in both cell lines by RT-PCR. Immunocytochemistry detected sst1, sst2A, sst2B, sst3, sst4 and sst5 protein expression in the membranes of both cell lines. Octreotide inhibited the proliferation of Caco-2 and HT-29 cells in a time and dose-dependent manner. Insulin exerted proliferative effects in Caco-2 cells and octreotide reversed its effect in both cell lines. Sodium orthovanadate suppressed the anti-proliferative effect of octreotide both in Caco-2 and HT-29 cells. Telomerase activity was significantly reduced when Caco-2 cells were exposed to octreotide, under serum-free cultured medium. On the other hand, telomerase attenuation after octreotide treatment could not counteract the actions of insulin on both cells. Our data indicate that the use of octreotide could provide a possible therapeutic approach to the management of certain patients who suffer from colon cancer.
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Affiliation(s)
- Georgios D Ayiomamitis
- Laboratory of Gastroenterology, School of Medicine, University of Crete, Heraklion, Greece ; 2nd Department of Surgery, Tzaneion General Hospital, Piraeus, Greece
| | - George Notas
- Laboratory of Gastroenterology, School of Medicine, University of Crete, Heraklion, Greece ; Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklion, Greece
| | - Apostolos Zaravinos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, Heraklion, Greece ; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Ioannis Drygiannakis
- Laboratory of Gastroenterology, School of Medicine, University of Crete, Heraklion, Greece
| | - Maria Georgiadou
- Laboratory of Gastroenterology, School of Medicine, University of Crete, Heraklion, Greece
| | - Ourania Sfakianaki
- Laboratory of Gastroenterology, School of Medicine, University of Crete, Heraklion, Greece
| | - Niki Mastrodimou
- Laboratory of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Kyriaki Thermos
- Laboratory of Pharmacology, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology, School of Medicine, University of Crete, Heraklion, Greece ; Department of Gastroenterology and Hepatology, School of Medicine, University of Crete, Heraklion, Greece
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46
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Baichoo E, Boardman LA. Toward a molecular classification of colorectal cancer: the role of telomere length. Front Oncol 2014; 4:158. [PMID: 24995160 PMCID: PMC4061573 DOI: 10.3389/fonc.2014.00158] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 06/05/2014] [Indexed: 11/19/2022] Open
Abstract
Telomere biology is central to the maintenance of genomic stability and telomeric dysfunction is thought to be an early stage in carcinogenesis. Reports of telomere lengths and their ascribed colorectal cancer (CRC) risks have been discordant, with both very short and very long telomeres implicated. Nevertheless, telomeres appear to play a very central role in cancer initiation. Telomere length changes also appear to impact disease burden, progression, and overall survival. This review covers contemporary views on telomere biology and CRC risk, with a brief overview of analytical methods employed in telomere measurement. We conclude with arguments in favor of including telomere assessment in the molecular profiling of CRCs.
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Affiliation(s)
- Esha Baichoo
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic , Rochester, MN , USA
| | - Lisa A Boardman
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic , Rochester, MN , USA
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47
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Knapp DW, Ramos-Vara JA, Moore GE, Dhawan D, Bonney PL, Young KE. Urinary Bladder Cancer in Dogs, a Naturally Occurring Model for Cancer Biology and Drug Development. ILAR J 2014; 55:100-18. [DOI: 10.1093/ilar/ilu018] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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48
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Cheng YB, Guo LP, Yao P, Ning XY, Aerken G, Fang DC. Telomerase and hTERT: Can they serve as markers for gastric cancer diagnosis? World J Gastroenterol 2014; 20:6615-6619. [PMID: 24914385 PMCID: PMC4047349 DOI: 10.3748/wjg.v20.i21.6615] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 02/15/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate telomerase activity and human telomerase reverse transcriptase (hTERT) expression in normal human gastric mucosal epithelial cells (nhGMECs) and fibroblasts (nhGMFs).
METHODS: nhGMECs and nhGMFs were isolated and cultured from specimens obtained during routine surgery for bleeding peptic ulcer. Telomerase activity in nhGMFs, nhGMECs, and the tumor cell lines BGC-823, SGC-7901 and MKN-28 cells was analyzed using the telomeric repeat amplification protocol assay. hTERT protein was determined in nhGMECs, nhGMFs, BGC-823, SGC-7901 and MKN-28 cells by indirect immunofluorescence.
RESULTS: A similar level of telomerase activity was observed in nhGMECs, nhGMFs and BGC-823, SGC-7901, MKN-28 cell lines. Positive hTERT immunostaining was detected in nhGMECs, nhGMFs, BGC-823, SGC-7901 and MKN-28 cell lines.
CONCLUSION: The use of telomerase or hTERT as diagnostic markers for gastric cancer may require further studies.
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49
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Ralla B, Stephan C, Meller S, Dietrich D, Kristiansen G, Jung K. Nucleic acid-based biomarkers in body fluids of patients with urologic malignancies. Crit Rev Clin Lab Sci 2014; 51:200-31. [PMID: 24878357 DOI: 10.3109/10408363.2014.914888] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This review focuses on the promising potential of nucleic acids in body fluids such as blood and urine as diagnostic, prognostic, predictive and monitoring biomarkers in urologic malignancies. The tremendous progress in the basic knowledge of molecular processes in cancer, as shown in the companion review on nucleic acid-based biomarkers in tissue of urologic tumors, provides a strong rationale for using these molecular changes as non-invasive markers in body fluids. The changes observed in body fluids are an integrative result, reflecting both tissue changes and processes occurring in the body fluids. The availability of sensitive methods has only recently made possible detailed studies of DNA- and RNA-based markers in body fluids. In addition to these biological aspects, methodological aspects of the determination of nucleic acids in body fluids, i.e. pre-analytical, analytical and post-analytical issues, are particularly emphasized. The characteristic changes of RNA (differential mRNA and miRNA expression) and DNA (concentrations, integrity index, mutations, microsatellite and methylation alterations) in serum/plasma and urine samples of patients suffering from the essential urologic cancers of the prostate, bladder, kidney and testis are summarized and critically discussed below. To translate the promising results into clinical practice, laboratory scientists and clinicians have to collaborate to resolve the challenges of harmonized and feasible pre-analytical and analytical conditions for the selected markers and to validate these markers in well-designed and sufficiently powered multi-center studies.
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Affiliation(s)
- Bernhard Ralla
- Department of Urology, Charité - Universitätsmedizin Berlin , Berlin , Germany
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50
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James MA, Vikis HG, Tate E, Rymaszewski AL, You M. CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis. Cancer Res 2013; 74:1116-27. [PMID: 24366883 DOI: 10.1158/0008-5472.can-13-1617] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The transmembrane protein CLPTM1L is overexpressed in non-small cell lung cancer, where it protects tumor cells from genotoxic apoptosis. Here, we show that RNA interference-mediated blockade of CLPTM1L inhibits K-Ras-induced lung tumorigenesis. CLPTM1L expression was required in vitro for morphologic transformation by H-RasV12 or K-RasV12, anchorage-independent growth, and survival of anoikis of lung tumor cells. Mechanistic investigations indicated that CLPTM1L interacts with phosphoinositide 3-kinase and is essential for Ras-induced AKT phosphorylation. Furthermore that the anti-apoptotic protein Bcl-xL is regulated by CLPTM1L independently of AKT activation. Constitutive activation of AKT or Bcl-xL rescued the transformed phenotype in CLPTM1L-depleted cells. The CLPTM1L gene lies within a cancer susceptibility locus at chromosome 5p15.33 defined by genome-wide association studies. The risk genotype at the CLPTM1L locus was associated with high expression of CLPTM1L in normal lung tissue, suggesting that cis-regulation of CLPTM1L may contribute to lung cancer risk. Taken together, our results establish a protumorigenic role for CLPTM1L that is critical for Ras-driven lung cancers, with potential implications for therapy and chemosensitization.
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Affiliation(s)
- Michael A James
- Authors' Affiliation: MCW Cancer Center, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin
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