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ZHAO SHUANG, WEN HONGYONG, WANG BAIQI, XIONG QINGLIN, LI LANXIN, CHENG AILAN. p53: A player in the tumor microenvironment. Oncol Res 2025; 33:795-810. [PMID: 40191727 PMCID: PMC11964878 DOI: 10.32604/or.2025.057317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/09/2024] [Indexed: 04/09/2025] Open
Abstract
Approximately half of all cancers have p53 inactivating mutations, in addition to which most malignancies inactivate the p53 pathway by increasing p53 inhibitors, decreasing p53 activators, or inactivating p53 downstream targets. A growing number of researches have demonstrated that p53 can influence tumor progression through the tumor microenvironment (TME). TME is involved in the process of tumor development and metastasis and affects the clinical prognosis of patients. p53 participates in host immunity and engages in the immune landscape of the TME, but the specific mechanisms remain to be investigated. This review briefly explores the interactions between different states of p53 and TME components and their mechanisms, as well as their effects on tumor progression. To understand the progress of drug development and clinical studies related to p53 and tumor microenvironment.
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Affiliation(s)
- SHUANG ZHAO
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - HONGYONG WEN
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - BAIQI WANG
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - QINGLIN XIONG
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - LANXIN LI
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - AILAN CHENG
- Hunan Engineering Research Center for Early Diagnosis and Treatment of Liver Cancer, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China
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Madeddu C, Lai E, Neri M, Sanna E, Gramignano G, Nemolato S, Scartozzi M, Giglio S, Macciò A. Association Between TP53 Mutations and Platinum Resistance in a Cohort of High-Grade Serous Ovarian Cancer Patients: Novel Implications for Personalized Therapeutics. Int J Mol Sci 2025; 26:2232. [PMID: 40076854 PMCID: PMC11901047 DOI: 10.3390/ijms26052232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/25/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
The integrity of p53 machinery is crucial for platinum activity, while p53 mutation is frequent in high-grade serous ovarian cancer (HGS-OC). This study aimed to evaluate the link between p53 mutations, platinum sensitivity (PS), and the platinum-free interval (PFI) in patients with HGS-OC. We prospectively analyzed 159 consecutive women with ovarian cancer who underwent surgery. The somatic mutational status of BRCA, HRD, and TP53 (according to structural, hotspot, and functional classification) was evaluated. Among enrolled patients, 82.4% of cases were TP53-mutated (MT), and 27.8% were BRCA-MT. The distribution of TP53 mutation categories did not differ significantly between the BRCA-MT and wild-type (WT) cases. In the entire population, the proportion of PS patients was significantly lower in TP53-MT compared to TP53-WT (p = 0.0208), in nonsense/frameshift/splicing compared to missense (p = 0.0319), and in loss-of-function (LOF) compared to GOF (p = 0.0048) MT cases. For the BRCA-MT patients, structural and functional TP53 mutations were not significantly different between the PS and PR patients. Conversely, for the BRCA WT patients, the distribution of structural and functional TP53 mutations significantly differed between PS and PR patients. In a multivariate regression analysis, LOF mutations were found to be independent negative predictors of PS (HR: 0.1717; 95% CI: 0.0661-0.4461; p-value: 0.0003). Kaplan-Meier curves showed a significantly lower PFI in cases with LOF mutations in the overall population (log-rank p = 0.0020) and in BRCA-WT patients (log-rank p = 0.0140). Via multivariate COX testing, it was found that LOF mutations were independently associated with a decreased PFI (p = 0.0036). In conclusion, our data show that HGS-OC harboring p53 LOF mutations is the poorest prognostic subgroup regarding PS and the PFI. Further studies are needed to confirm our findings.
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Affiliation(s)
- Clelia Madeddu
- Medical Oncology Unit, Department of Medical Sciences and Public Health, University Hospital Cagliari, University of Cagliari, 09100 Cagliari, Italy; (E.L.); (M.S.)
| | - Eleonora Lai
- Medical Oncology Unit, Department of Medical Sciences and Public Health, University Hospital Cagliari, University of Cagliari, 09100 Cagliari, Italy; (E.L.); (M.S.)
| | - Manuela Neri
- Gynecologic Oncology Unit, ARNAS G. Brotzu, Department of Surgical Sciences, University of Cagliari, 09100 Cagliari, Italy; (M.N.); (E.S.)
| | - Elisabetta Sanna
- Gynecologic Oncology Unit, ARNAS G. Brotzu, Department of Surgical Sciences, University of Cagliari, 09100 Cagliari, Italy; (M.N.); (E.S.)
| | - Giulia Gramignano
- Medical Oncology Unit, San Gavino Hospital, 09037 San Gavino, Italy;
| | - Sonia Nemolato
- Department of Pathology, ARNAS G. Brotzu, 09100 Cagliari, Italy;
| | - Mario Scartozzi
- Medical Oncology Unit, Department of Medical Sciences and Public Health, University Hospital Cagliari, University of Cagliari, 09100 Cagliari, Italy; (E.L.); (M.S.)
| | - Sabrina Giglio
- Medical Genetics Unit, Department of Medical Sciences and Public Health, R. Binaghi Hospital, University of Cagliari, ASL 8, 09100 Cagliari, Italy;
| | - Antonio Macciò
- Gynecologic Oncology Unit, ARNAS G. Brotzu, Department of Surgical Sciences, University of Cagliari, 09100 Cagliari, Italy; (M.N.); (E.S.)
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Fernandes Q, Therachiyil L, Younis SM, Dermime S, Al Moustafa AE. Oncoproteins E6/E7 of the human papillomavirus types 16 & 18 synergize in modulating oncogenes and tumor suppressor proteins in colorectal cancer. Expert Rev Proteomics 2025; 22:71-84. [PMID: 39815804 DOI: 10.1080/14789450.2025.2455104] [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: 01/18/2024] [Revised: 11/04/2024] [Accepted: 01/11/2025] [Indexed: 01/18/2025]
Abstract
OBJECTIVE Our study presents a novel analysis of the oncogenes and tumor suppressor proteins directly modulated by E6/E7 of high-risk HPV types 16 and 18, in colorectal cancer (CRC). METHODS HCT 116 (KRAS mutant) & HT-29 (TP53 mutant) cell models of CRC were transduced with E6/E7 of HPV16 and HPV18, individually and in combination. Further, we utilized a liquid chromatography mass spectrometry (LC-MS/MS) approach to analyze and compare the proteomes of both CRC cell models. RESULTS We generated six stably transduced cell lines. Our data revealed a significantly higher, HPV-induced modulation of oncogenes and tumor suppressor proteins in the TP53 mutant model, as compared to the KRAS mutant model (p ≤ 0.01). Less than 1% of the genes were commonly modulated by HPV, between both models. We also report that HT-29 cells, expressing E6/E7 of both HPV types, significantly reduced the suppression of oncogenes as compared to cells expressing E6/E7 of either HPV types individually (p-value ≤0.00001). CONCLUSION Our data imply that HPV coinfections leads to the sustenance of a pro-oncogenic environment in CRC. HPV modulates different oncogenes/tumor suppressor proteins in CRC of varying mutational backgrounds, thus highlighting the importance of personalized therapies for such diseases with mutational heterogeneity.
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Affiliation(s)
- Queenie Fernandes
- College of Medicine, QU Health, Qatar University, Doha, Qatar
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Shahd M Younis
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Said Dermime
- Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Ala-Eddin Al Moustafa
- College of Medicine, QU Health, Qatar University, Doha, Qatar
- Biomedical Research Center, QU Health, Qatar University, Doha, Qatar
- Oncology Department, McGill University, Montreal, Quebec, Canada
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Vargas-Madriz ÁF, Kuri-García A, Luzardo-Ocampo I, Ferriz-Martínez RA, García-Gasca T, Saldaña C, Vargas-Madriz H, Guzmán-Maldonado SH, Chávez-Servín JL. Effect of Drying Methods on the Phenolic Profile and Antioxidant Capacity of Pithecellobium dulce (Roxb.) Benth. Aril and Its Inhibitory Properties on Human SW480 Colon Adenocarcinoma Cells. Molecules 2025; 30:233. [PMID: 39860103 PMCID: PMC11767361 DOI: 10.3390/molecules30020233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 01/03/2025] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Pithecellobium dulce (P. dulce) is a Mexican plant that is consumed raw or in different preparations, and its anti-inflammatory and antioxidant properties have traditionally been useful in treating several conditions. However, the post-harvest drying process can alter the content of bioactive compounds in P. dulce. This study aims to evaluate the impact of different drying methods on the phenolic profile and antioxidant capacity of this plant, as well as its inhibitory effect on human SW480 colon adenocarcinoma cells. After oven drying, the samples showed a higher amount (p < 0.05) of phenolic compounds, up to 1149.45 ± 69.27 mg GAE/100 g LE, which is 80% more than the freeze-dried samples. Also, the antioxidant capacity was higher in oven-dried samples, with 44.63 ± 2.00 µmol Trolox equivalents/g LE, 108% more than the freeze-dried method. Methanolic extraction, in turn, yielded better results than aqueous and ethanolic extractions. Up to 14 polyphenolic compounds were detected in oven-dried samples. For in vitro assays in SW480 cells, the 50% v/v methanolic extract was used. From this extract, the median lethal concentration (LC50) was determined to be 13.76 mg/mL, which represents the concentration necessary to inhibit the growth of half of the cancer cells of this cell line. The extract led to cell cycle arrest in the G1 phase and an increase in apoptosis-induced cell death. The P. dulce extract augmented p53 and decreased KRAS gene expressions. Results suggested pro-apoptotic mechanisms in colon cancer cells in vitro linked to P. dulce bioactive compounds, which are better preserved when oven-dried plants are subjected to methanolic extraction.
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Affiliation(s)
- Ángel Félix Vargas-Madriz
- Laboratorio de Biología Celular y Molecular, School of Natural Sciences, Universidad Autonoma de Queretaro, Av. de las Ciencias S/N, Juriquilla, Queretaro 76230, Mexico; (Á.F.V.-M.); (A.K.-G.); (R.A.F.-M.); (T.G.-G.)
| | - Aarón Kuri-García
- Laboratorio de Biología Celular y Molecular, School of Natural Sciences, Universidad Autonoma de Queretaro, Av. de las Ciencias S/N, Juriquilla, Queretaro 76230, Mexico; (Á.F.V.-M.); (A.K.-G.); (R.A.F.-M.); (T.G.-G.)
| | - Ivan Luzardo-Ocampo
- Institute for Obesity Research, Tecnológico de Monterrey, Av. Eugenio Garza Sada 2501, Monterrey 64841, Mexico;
- School of Engineering and Sciences, Tecnologico de Monterrey, Av. General Ramón Corona 2514, Zapopan 45138, Mexico
| | - Roberto Augusto Ferriz-Martínez
- Laboratorio de Biología Celular y Molecular, School of Natural Sciences, Universidad Autonoma de Queretaro, Av. de las Ciencias S/N, Juriquilla, Queretaro 76230, Mexico; (Á.F.V.-M.); (A.K.-G.); (R.A.F.-M.); (T.G.-G.)
| | - Teresa García-Gasca
- Laboratorio de Biología Celular y Molecular, School of Natural Sciences, Universidad Autonoma de Queretaro, Av. de las Ciencias S/N, Juriquilla, Queretaro 76230, Mexico; (Á.F.V.-M.); (A.K.-G.); (R.A.F.-M.); (T.G.-G.)
| | - Carlos Saldaña
- Laboratorio de Biofísica de Membranas y Nanotecnología and Laboratorio Nacional de Visualización Científica Avanzada (LAVIS), School of Natural Sciences, Universidad Autonoma de Queretaro, Av. de las Ciencias S/N, Juriquilla, Queretaro 76230, Mexico;
| | - Haidel Vargas-Madriz
- Departamento de Producción Agrícola, Centro Universitario de la Costa Sur, Universidad de Guadalajara—UDG, Av. Independencia Nacional 141, Guadalajara 48900, Mexico;
| | - Salvador Horacio Guzmán-Maldonado
- Laboratorio de Alimentos, Centro de Investigación Regional del Centro, Instituto Nacional de Investigaciones Forestales, Agrícolas y Pecuarias (INIFAP), Campos Experimental Bajío, Km. 6, Carr. Celaya-San Miguel de Allende, Celaya 38810, Mexico;
| | - Jorge Luis Chávez-Servín
- Laboratorio de Biología Celular y Molecular, School of Natural Sciences, Universidad Autonoma de Queretaro, Av. de las Ciencias S/N, Juriquilla, Queretaro 76230, Mexico; (Á.F.V.-M.); (A.K.-G.); (R.A.F.-M.); (T.G.-G.)
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Nzitakera A, Uwamariya D, Kato H, Surwumwe JB, Mbonigaba A, Ndoricyimpaye EL, Uwamungu S, Manirakiza F, Ndayisaba MC, Ntakirutimana G, Seminega B, Dusabejambo V, Rutaganda E, Kamali P, Ngabonziza F, Ishikawa R, Watanabe H, Rugwizangoga B, Baba S, Yamada H, Yoshimura K, Sakai Y, Sugimura H, Shinmura K. TP53 mutation status and consensus molecular subtypes of colorectal cancer in patients from Rwanda. BMC Cancer 2024; 24:1266. [PMID: 39394554 PMCID: PMC11468329 DOI: 10.1186/s12885-024-13009-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 09/30/2024] [Indexed: 10/13/2024] Open
Abstract
BACKGROUND Mutations in the TP53 tumor suppressor gene are well-established drivers of colorectal cancer (CRC) development. However, data on the prevalence of TP53 variants and their association with consensus molecular subtype (CMS) classification in patients with CRC from Rwanda are currently lacking. This study addressed this knowledge gap by investigating TP53 mutation status concerning CMS classification in a CRC cohort from Rwanda. METHODS Formalin-fixed paraffin-embedded (FFPE) tissue blocks were obtained from 51 patients with CRC at the University Teaching Hospital of Kigali, Rwanda. Exons 4 to 11 and their flanking intron-exon boundaries in the TP53 gene were sequenced using Sanger sequencing to identify potential variants. The recently established immunohistochemistry-based classifier was employed to determine the CMS of each tumor. RESULTS Sequencing analysis of cancerous tissue DNA revealed TP53 pathogenic variants in 23 of 51 (45.1%) patients from Rwanda. These variants were predominantly missense types (18/23, 78.3%). The most frequent were c.455dup (p.P153Afs*28), c.524G > A (p.R175H), and c.733G > A (p.G245S), each identified in three tumors. Trinucleotide sequence context analysis of the 23 mutations (20 of which were single-base substitutions) revealed a predominance of the [C > N] pattern among single-base substitutions (SBSs) (18/20; 90.0%), with C[C > T]G being the most frequent mutation (5/18, 27.8%). Furthermore, pyrimidine bases (C and T) were preferentially found at the 5' flanking position of the mutated cytosine (13/18; 72.2%). Analysis of CMS subtypes revealed the following distribution: CMS1 (microsatellite instability-immune) (6/51, 11.8%), CMS2 (canonical) (28/51, 54.9%), CMS3 (metabolic) (9/51, 17.6%), and CMS4 (mesenchymal) (8/51, 15.7%). Interestingly, the majority of TP53 variants were in the CMS2 subgroup (14/23; 60.1%). CONCLUSION Our findings indicate a high frequency of TP53 variants in CRC patients from Rwanda. Importantly, these variants are enriched in the CMS2 subtype. This study, representing the second investigation into molecular alterations in patients with CRC from Rwanda and the first to explore TP53 mutations and CMS classification, provides valuable insights into the molecular landscape of CRC in this understudied population.
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Affiliation(s)
- Augustin Nzitakera
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
- Department of Biomedical Laboratory Sciences, School of Health Sciences, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
| | - Delphine Uwamariya
- Department of Biomedical Laboratory Sciences, School of Health Sciences, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
- Department of Pathology, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- Department of Pathology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
| | - Hisami Kato
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Jean Bosco Surwumwe
- Department of Pathology, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
| | - André Mbonigaba
- Department of Pathology, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- Department of Pathology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
| | - Ella Larissa Ndoricyimpaye
- Department of Biomedical Laboratory Sciences, School of Health Sciences, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
- Université Catholique de Louvain, Médecine Expérimentale, Brussels, 1348, Belgium
| | - Schifra Uwamungu
- Department of Biomedical Laboratory Sciences, School of Health Sciences, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
- Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SE-40530, Sweden
| | - Felix Manirakiza
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
- Department of Pathology, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- Department of Pathology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
| | - Marie Claire Ndayisaba
- Department of Pathology, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- Department of Pathology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
| | - Gervais Ntakirutimana
- Department of Pathology, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- Department of Pathology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
| | - Benoit Seminega
- Department of Internal Medicine, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- College of Medicine and Health Sciences, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda
| | - Vincent Dusabejambo
- Department of Internal Medicine, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- College of Medicine and Health Sciences, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda
| | - Eric Rutaganda
- Department of Internal Medicine, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- College of Medicine and Health Sciences, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda
| | - Placide Kamali
- Department of Internal Medicine, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- College of Medicine and Health Sciences, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda
| | - François Ngabonziza
- Department of Internal Medicine, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- College of Medicine and Health Sciences, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda
| | - Rei Ishikawa
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Hirofumi Watanabe
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Belson Rugwizangoga
- Department of Pathology, University Teaching Hospital of Kigali, P.O. Box 655, Kigali, Rwanda
- Department of Pathology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, P.O. Box 3286, Kigali, Rwanda
- Tumor Immunology Laboratory, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SE- 40530, Sweden
| | - Satoshi Baba
- Department of Diagnostic Pathology, Hamamatsu University School of Medicine, Medicine, 1- 20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Hidetaka Yamada
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Katsuhiro Yoshimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Yasuhiro Sakai
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Haruhiko Sugimura
- Sasaki Institute Sasaki Foundation, 2-2 Kanda Surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
| | - Kazuya Shinmura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
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Yan H, Shen X, Yao Y, Khan SA, Ma S, Johnson CH. A machine learning and drug repurposing approach to target ferroptosis in colorectal cancer stratified by sex and KRAS. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.24.600340. [PMID: 38979294 PMCID: PMC11230177 DOI: 10.1101/2024.06.24.600340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
The landscape of sex differences in Colorectal Cancer (CRC) has not been well characterized with respect to the mechanisms of action for oncogenes such as KRAS. However, our recent study showed that tumors from male patients with KRAS mutations have decreased iron-dependent cell death called ferroptosis. Building on these findings, we further examined ferroptosis in CRC, considering both sex of the patient and KRAS mutations, using public databases and our in-house CRC tumor cohort. Through subsampling inference and variable importance analysis (VIMP), we identified significant differences in gene expression between KRAS mutant and wild type tumors from male patients. These genes suppress (e.g., SLC7A11 ) or drive (e.g., SLC1A5 ) ferroptosis, and these findings were further validated with Gaussian mixed models. Furthermore, we explored the prognostic value of ferroptosis regulating genes and discovered sex- and KRAS-specific differences at both the transcriptional and metabolic levels by random survival forest with backward elimination algorithm (RSF-BE). Of note, genes and metabolites involved in arginine synthesis and glutathione metabolism were uniquely associated with prognosis in tumors from males with KRAS mutations. Additionally, drug repurposing is becoming popular due to the high costs, attrition rates, and slow pace of new drug development, offering a way to treat common and rare diseases more efficiently. Furthermore, increasing evidence has shown that ferroptosis inhibition or induction can improve drug sensitivity or overcome chemotherapy drug resistance. Therefore, we investigated the correlation between gene expression, metabolite levels, and drug sensitivity across all CRC primary tumor cell lines using data from the Genomics of Drug Sensitivity in Cancer (GDSC) resource. We observed that ferroptosis suppressor genes such as DHODH , GCH1 , and AIFM2 in KRAS mutant CRC cell lines were resistant to cisplatin and paclitaxel, underscoring why these drugs are not effective for these patients. The comprehensive map generated here provides valuable biological insights for future investigations, and the findings are supported by rigorous analysis of large-scale publicly available data and our in-house cohort. The study also emphasizes the potential application of VIMP, Gaussian mixed models, and RSF-BE models in the multi-omics research community. In conclusion, this comprehensive approach opens doors for leveraging precision molecular feature analysis and drug repurposing possibilities in KRAS mutant CRC.
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Jiang H, Li X, Zhou F, Xi Y, Xu G. HMGA2 promotes resistance against paclitaxel by targeting the p53 signaling pathway in colorectal cancer cells. Heliyon 2024; 10:e31431. [PMID: 38845972 PMCID: PMC11154217 DOI: 10.1016/j.heliyon.2024.e31431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 04/27/2024] [Accepted: 05/15/2024] [Indexed: 06/09/2024] Open
Abstract
Colorectal cancer is one of the most common malignancies and ranks second in terms of cancer-related mortality worldwide due to its metastasis, drug resistance, and reoccurrence. High-mobility gene group A2 (HMGA2) is overexpressed in colorectal cancer, contributing to the aggressiveness of tumor malignance, and promotes drug resistance in many types of cancer. However, the underlying molecular mechanism of HMGA2 is yet to be elucidated. In this study, we showed that HMGA2 is overexpressed in colorectal cancer tissue, and knockdown of HMGA2 significantly inhibited colorectal cancer cell growth and migratory capability. HMGA2 regulates the cancer cell response to a widely used anti-cancer drug, paclitaxel (PTX). HMGA2 knockdown increased cell death, whereas HMGA2 overexpression decreased cell death after PTX treatment. Furthermore, lower reactive oxygen species (ROS) levels and mitochondrial potential were detected in HMGA2 overexpression cells after PTX treatment. However, HMGA2 knockdown produced the opposite effect. RNA sequencing showed a p53 signaling pathway-dependent regulation in HMGA2 knockdown cells. Combined with p53 inhibitors and HMGA2 knockdown, a synergetic effect of more cell death was observed in colorectal cancer cells after PTX treatment. Thus, we showed that HMGA2 can activate p53 signaling to regulate colorectal cancer cell death after PTX treatment. Altogether, our results reveal novel insights into the molecular mechanisms underlying HMGA2-mediated cancer cell resistance against PTX and highlight the potential of targeting HMGA2 and p53 signaling for the therapeutic investigation of colorectal cancer.
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Affiliation(s)
- Haizhong Jiang
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China
- Department of Gastroenterology, First Affiliated Hospital, Ningbo University, Ningbo, Zhejiang, 315000, China
| | - Xueying Li
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China
- Department of Gastroenterology, First Affiliated Hospital, Ningbo University, Ningbo, Zhejiang, 315000, China
| | - Feng Zhou
- Department of Gastroenterology, First Affiliated Hospital, Ningbo University, Ningbo, Zhejiang, 315000, China
| | - Yang Xi
- Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Guoqiang Xu
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, 310003, Hangzhou, China
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Cecchi D, Jackson N, Beckham W, Chithrani DB. Improving the Efficacy of Common Cancer Treatments via Targeted Therapeutics towards the Tumour and Its Microenvironment. Pharmaceutics 2024; 16:175. [PMID: 38399237 PMCID: PMC10891984 DOI: 10.3390/pharmaceutics16020175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/19/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Cancer is defined as the uncontrolled proliferation of heterogeneous cell cultures in the body that develop abnormalities and mutations, leading to their resistance to many forms of treatment. Left untreated, these abnormal cell growths can lead to detrimental and even fatal complications for patients. Radiation therapy is involved in around 50% of cancer treatment workflows; however, it presents significant recurrence rates and normal tissue toxicity, given the inevitable deposition of the dose to the surrounding healthy tissue. Chemotherapy is another treatment modality with excessive normal tissue toxicity that significantly affects patients' quality of life. To improve the therapeutic efficacy of radiotherapy and chemotherapy, multiple conjunctive modalities have been proposed, which include the targeting of components of the tumour microenvironment inhibiting tumour spread and anti-therapeutic pathways, increasing the oxygen content within the tumour to revert the hypoxic nature of the malignancy, improving the local dose deposition with metal nanoparticles, and the restriction of the cell cycle within radiosensitive phases. The tumour microenvironment is largely responsible for inhibiting nanoparticle capture within the tumour itself and improving resistance to various forms of cancer therapy. In this review, we discuss the current literature surrounding the administration of molecular and nanoparticle therapeutics, their pharmacokinetics, and contrasting mechanisms of action. The review aims to demonstrate the advancements in the field of conjugated nanomaterials and radiotherapeutics targeting, inhibiting, or bypassing the tumour microenvironment to promote further research that can improve treatment outcomes and toxicity rates.
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Affiliation(s)
- Daniel Cecchi
- Department of Physics and Astronomy, University of Victoria, Victoria, BC V8P 5C2, Canada; (D.C.)
| | - Nolan Jackson
- Department of Physics and Astronomy, University of Victoria, Victoria, BC V8P 5C2, Canada; (D.C.)
| | - Wayne Beckham
- Department of Physics and Astronomy, University of Victoria, Victoria, BC V8P 5C2, Canada; (D.C.)
- British Columbia Cancer-Victoria, Victoria, BC V8R 6V5, Canada
| | - Devika B. Chithrani
- Department of Physics and Astronomy, University of Victoria, Victoria, BC V8P 5C2, Canada; (D.C.)
- Centre for Advanced Materials and Related Technologies, Department of Chemistry, University of Victoria, Victoria, BC V8P 5C2, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada
- Department of Computer Science, Mathematics, Physics and Statistics, Okanagan Campus, University of British Columbia, Kelowna, BC V1V 1V7, Canada
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9
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Dadgar-Zankbar L, Shariati A, Bostanghadiri N, Elahi Z, Mirkalantari S, Razavi S, Kamali F, Darban-Sarokhalil D. Evaluation of enterotoxigenic Bacteroides fragilis correlation with the expression of cellular signaling pathway genes in Iranian patients with colorectal cancer. Infect Agent Cancer 2023; 18:48. [PMID: 37644520 PMCID: PMC10463534 DOI: 10.1186/s13027-023-00523-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common cancers all over the world, and dysbiosis in the gut microbiota may play a role in colorectal carcinogenesis. Bacteroides fragilis can lead to tumorigenesis by changing signaling pathways, including the WNT/β-catenin pathway. Therefore, in the present study, we investigated the correlation between the enterotoxigenic B. fragilis amount and the expression of signaling pathway genes involved in CRC. MATERIALS AND METHODS B. fragilis was determined in 30 tumors and adjacent healthy tissues by the qPCR method. Next, the relationship between enterotoxigenic B. fragilis and the expression of signaling pathway genes, including CCND1, TP53, BCL2, BAX, WNT, TCF, AXIN, APC, and CTNNB1 was investigated. Additionally, possible correlations between clinicopathological features of the tumor samples and the abundance of B. fragilis were analyzed. RESULTS The results showed that B. fragilis was detected in 100% of tumor samples and 86% of healthy tissues. Additionally, enterotoxigenic B. fragilis colonized 47% of all samples, and bft-1 toxin was the most frequently found isotype among the samples. The analysis showed that the high level of B. fragilis has a significant relationship with the high expression of AXIN, CTNNB1, and BCL2 genes. On the other hand, our results did not show any possible correlation between this bacterium and the clinicopathological features of the tumor sample. CONCLUSION B. fragilis had a higher abundance in the tumor samples than in healthy tissues, and this bacterium may lead to CRC by making changes in cellular signaling pathways and genes. Therefore, to better understand the physiological effects of B. fragilis on the inflammatory response and CRC, future research should focus on dissecting the molecular mechanisms by which this bacterium regulates cellular signaling pathways.
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Affiliation(s)
- Leila Dadgar-Zankbar
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Aref Shariati
- Molecular and Medicine Research Center, Khomein University of Medical Sciences, Khomein, Iran
- Student Research Committee, Khomein University of Medical Sciences, Khomein, Iran
| | - Narjess Bostanghadiri
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Elahi
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shiva Mirkalantari
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shabnam Razavi
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Kamali
- Iran National Tumor Bank, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Darban-Sarokhalil
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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10
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Shomali N, Kamrani A, Nasiri H, Heris JA, Shahabi P, Yousefi M, Mohammadinasab R, Sadeghvand S, Akbari M. An updated review of a novel method for examining P53 mutations in different forms of cancer. Pathol Res Pract 2023; 248:154585. [PMID: 37302277 DOI: 10.1016/j.prp.2023.154585] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/27/2023] [Accepted: 05/28/2023] [Indexed: 06/13/2023]
Abstract
In the past fifteen years, it has been clear that tumor-associated p53 mutations can cause behaviors distinct from those brought on by a simple loss of p53's tumor-suppressive function in its wild-type form. Many of these mutant p53 proteins develop oncogenic characteristics that allow them to encourage cell survival, invasion, and metastasis. But it is now understood that the immune response is also significantly influenced by the cancer cell's p53 status. The recruitment and activity of myeloid and T cells can be impacted by p53 loss or mutation in malignancies, allowing immune evasion and accelerating cancer growth. Additionally, p53 can work in immune cells, which can have various effects that either hinder or assist the growth of tumors. In this review article, we examined different mutations of P53 in some significant cancers, such as liver, colorectal, and prostate, and reviewed some new therapeutic approaches.
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Affiliation(s)
- Navid Shomali
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Amin Kamrani
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Nasiri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parviz Shahabi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Mohammadinasab
- Department of History of Medicine, School of Traditional Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Sadeghvand
- Pediatrics Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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11
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Zhang Y, Guo T, Li S, Ren Z, Gao S, Lu H, Ma X, Liu D, Liu Y, Kong D, Qiu Y. Anticancer efficacy of hirsuteine against colorectal cancer by opposite modulation of wild-type and mutant p53. Discov Oncol 2023; 14:84. [PMID: 37256374 DOI: 10.1007/s12672-023-00688-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/10/2023] [Indexed: 06/01/2023] Open
Abstract
PURPOSE The present study aimed to explore the anticancer activity of hirsuteine (HST), an indole alkaloid from the traditional Chinese herbal medicine Uncaria rhynchophylla, against colorectal cancer (CRC) and the underlining mechanism. METHODS MTT, colony formation, flow cytometry and MDC staining were conducted to confirm the antiproliferative effect of HST on human CRC cells harboring different p53 status. Protein expressions were evaluated by the Western blot analysis. p53 protein half-life and the interaction between p53 and MDM2 were investigated using cycloheximide (CHX)-chase assay and Co-immunoprecipitation (Co-IP), respectively. Transcriptional activity of p53 was examined by qRT-PCR and Chromatin immunoprecipitation (ChIP). Xenograft tumor in nude mice was created to evaluate in vivo anticancer effect of HST against CRC. RESULTS HST inhibited cell growth, arrested cell cycle and induced autophagy, showing efficient anticancer effects on CRC cells independent of p53 status. In HCT-8 cells, HST prolonged wtp53 half-life, and upregulated mRNA level of p21, suggesting that HST activated the p53 pathway through enhancement of wtp53 stability and transcriptional activity. Meanwhile in SW620 cells, HST induced MDM2-mediated proteasomal degradation of mutp53R273H, increased the DNA-binding ability of mutp53R273H at the p21 promoter, and upregulated mRNA levels of p21 and MDM2, demonstrating the depletion of mutp53R273H and restoration of its wild-type-like properties by HST. p53 knockdown by siRNA significantly impaired the growth inhibition of HST on HCT-8 and SW620 cells. Moreover, HST showed anticancer effects in xenograft tumors, accompanied with an opposite regulation of wtp53 and mutp53 R273H in mechanism. CONCLUSION This study revealed the anticancer efficacy of HST against CRC via opposite modulation of wtp53 and mutp53 R273H, indicating the potential of HST to be a CRC drug candidate targeting p53 signaling.
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Affiliation(s)
- Yan Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Tingting Guo
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Shurong Li
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Zehao Ren
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Shan Gao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Hao Lu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Xuelan Ma
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Donghui Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Yao Liu
- Department of Otorhinolaryngology Head and Neck Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.
| | - Yuling Qiu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.
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Hu WH, Liu TT, Liu PF, Morgan P, Lin IL, Tsai WL, Cheng YY, Hsieh AT, Hu TH, Shu CW. ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer. Cancer Cell Int 2023; 23:63. [PMID: 37038218 PMCID: PMC10088137 DOI: 10.1186/s12935-023-02909-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 03/27/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Autophagy related protease 4B (ATG4B) is a protease required for autophagy processing, which is strongly implicated in cancer progression. Phosphorylation of ATG4B is crucial for activation of its protease activity. However, little is known about the relationship of ATG4B and its phosphorylated form at Ser 383 and 392 sites (pS383/392-ATG4B), with clinical outcomes, particularly in colorectal cancer (CRC). METHODS The ATG4B gene expression in CRC patients was obtained from The Cancer Genome Atlas (TCGA) database to analyze its clinical relevance. Tissue microarrays composed of 118 CRC patient specimens were used to determine the associations of ATG4B and pS383/392-ATG4B protein levels with prognosis. The biological functions of ATG4B in CRC cells were inspected with cell proliferation, mobility and spheroid culture assays. RESULTS ATG4B gene expression was elevated in tumor tissues of CRC patients compared to that in adjacent normal tissues and high level of ATG4B expression was associated with poor survival. Similarly, protein levels of ATG4B and pS383/392-ATG4B were highly correlated with worse overall survival and disease-free survival. Stratification analysis results showed that high level of ATG4B had significantly higher risk of mortality in males and elderly patients compared to those female patients and patients 60 years or younger. In contrast, multivariate Cox's regression analysis indicated that high level of pS383/392-ATG4B was significantly linked to unfavorable overall survival and disease-free survival of males and elderly patients, whereas, it had no correlation with female patients and patients 60 years or younger. Moreover, high level of ATG4B was positively associated with increased mortality risk in patients with advanced AJCC stages (III and IV) and lymph node invasion (N1 and N2) for both overall survival and disease-free survival. Nevertheless, high level of pS383/392-ATG4B was positively correlated with increased mortality risk in patients with early AJCC stages (I and II) and without lymph node invasion (N0). In addition, silencing ATG4B attenuated migration, invasion, and further enhanced the cytotoxic effects of chemotherapeutic drugs in two and three-dimensional cultures of CRC cells. CONCLUSIONS Our results suggest that ATG4B and pS383/392-ATG4B might be suitable biomarkers and therapeutic targets for CRC.
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Affiliation(s)
- Wan-Hsiang Hu
- Department of Colorectal Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83341, Taiwan
- Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Kaohsiung, 83341, Taiwan
| | - Ting-Ting Liu
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83341, Taiwan
| | - Pei-Feng Liu
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan
| | - Paul Morgan
- Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - I-Ling Lin
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan
| | - Wei-Lun Tsai
- Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, 81362, Taiwan
| | - Yi-Yun Cheng
- Innovative Incubation Center, Praexisio Taiwain Inc, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Ang-Tsen Hsieh
- Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, No. 70, Lianhai Rd., Gushan Dist, Kaohsiung, 80424, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan
| | - Chih-Wen Shu
- Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, No. 70, Lianhai Rd., Gushan Dist, Kaohsiung, 80424, Taiwan.
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
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13
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Ghorbani Z, Heidari M, Jafarinia M, Rohani M, Akbari A. Transcriptional Regulation of the Colorectal Cancer Stem Cell Markers, Nanog and Oct4, Induced by a Thermodynamic-Based Therapy Approach. IRANIAN JOURNAL OF PUBLIC HEALTH 2023; 52:848-856. [PMID: 37551178 PMCID: PMC10404326 DOI: 10.18502/ijph.v52i4.12458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/10/2022] [Indexed: 08/09/2023]
Abstract
Background Cancer stem cells (CSC), as responsible issues to cancer development and progression, play a crucial role in tumorigenesis, recurrence, metastasis, and chemoresistance. Both hyperthermia and photodynamic therapy (PDT) may be effective for cancer treatment, particularly when combined with other therapeutic approaches. This study aimed to evaluate the effect of hyperthermia combined with PDT on colorectal CSC and the gene expression of the CSC markers, presenting a more effective approach for cancer therapy. Methods The study was conducted in the Pasteur institute of Iran, Tehran, Iran in 2018. We evaluated the anticancer role of hyperthermia, Gold nanoparticles coated with curcumin (Cur-GNPs) in PDT and combination of the two approaches on cell viability and the expression of CSC markers, Nanog and Oct4 in colorectal cancer cell line HT-29. The cytotoxicity effect of Cur-GNPs against the cells was assessed in vitro. The cell viability was assessed using MTT assay, and the expression analysis of the CSC genes was evaluated using a q-real-time PCR. Results Cell viability was decreased by PDT (P=0.015) and the combination therapy (P=0.006) but not by hyperthermia alone (P=0.4), compared to control. Also, the expression of CSC markers, Nanog and Oct4 was shown to significantly down-regulate in all hyperthermia, PDT and combination groups. Conclusion Hyperthermia combined with PDT was indicated to be more efficient in eliminating tumors than hyperthermia or PDT alone.
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Affiliation(s)
- Zakieh Ghorbani
- Department of Molecular Genetics, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran
- Department of Molecular Genetics, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | - Mansour Heidari
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Jafarinia
- Department of Molecular Genetics, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran
- Department of Molecular Genetics, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | - Mahdi Rohani
- Department of Microbiology, Pasteur Institute of Iran, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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14
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Liang H, He X, Tong Y, Bai N, Pu Y, Han K, Wang Y. Ferroptosis open a new door for colorectal cancer treatment. Front Oncol 2023; 13:1059520. [PMID: 37007121 PMCID: PMC10061081 DOI: 10.3389/fonc.2023.1059520] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 02/21/2023] [Indexed: 03/18/2023] Open
Abstract
Colorectal cancer (CRC) is the third highest incidence and the second highest mortality malignant tumor in the world. The etiology and pathogenesis of CRC are complex. Due to the long course of the disease and no obvious early symptoms, most patients are diagnosed as middle and late stages. CRC is prone to metastasis, most commonly liver metastasis, which is one of the leading causes of death in CRC patients. Ferroptosis is a newly discovered cell death form with iron dependence, which is driven by excessive lipid peroxides on the cell membrane. It is different from other form of programmed cell death in morphology and mechanism, such as apoptosis, pyroptosis and necroptosis. Numerous studies have shown that ferroptosis may play an important role in the development of CRC. For advanced or metastatic CRC, ferroptosis promises to open a new door in the setting of poor response to chemotherapy and targeted therapy. This mini review focuses on the pathogenesis of CRC, the mechanism of ferroptosis and the research status of ferroptosis in CRC treatment. The potential association between ferroptosis and CRC and some challenges are discussed.
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Affiliation(s)
- Hong Liang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xia He
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yitong Tong
- Chengdu Second People’s Hospital Party Committee Office, Chengdu, China
| | - Niuniu Bai
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- School of Pharmacy, Shanxi Medical University, Taiyuan, China
| | - Yushu Pu
- Nanchang University Queen Mary School, Nanchang, China
| | - Ke Han
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Pharmacy, The First People’s Hospital of Chengdu, Chengdu, China
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sicuhan, China
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15
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Abbes S, Baldi S, Sellami H, Amedei A, Keskes L. Molecular methods for colorectal cancer screening: Progress with next-generation sequencing evolution. World J Gastrointest Oncol 2023; 15:425-442. [PMID: 37009313 PMCID: PMC10052664 DOI: 10.4251/wjgo.v15.i3.425] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/02/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023] Open
Abstract
Currently, colorectal cancer (CRC) represents the third most common malignancy and the second most deadly cancer worldwide, with a higher incidence in developed countries. Like other solid tumors, CRC is a heterogeneous genomic disease in which various alterations, such as point mutations, genomic rearrangements, gene fusions or chromosomal copy number alterations, can contribute to the disease development. However, because of its orderly natural history, easily accessible onset location and high lifetime incidence, CRC is ideally suited for preventive intervention, but the many screening efforts of the last decades have been compromised by performance limitations and low penetrance of the standard screening tools. The advent of next-generation sequencing (NGS) has both facilitated the identification of previously unrecognized CRC features such as its relationship with gut microbial pathogens and revolutionized the speed and throughput of cataloguing CRC-related genomic alterations. Hence, in this review, we summarized the several diagnostic tools used for CRC screening in the past and the present, focusing on recent NGS approaches and their revolutionary role in the identification of novel genomic CRC characteristics, the advancement of understanding the CRC carcinogenesis and the screening of clinically actionable targets for personalized medicine.
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Affiliation(s)
- Salma Abbes
- Laboratory of Parasitic and Fungal Molecular Biology, University of Sfax, Sfax 3029, Tunisia
| | - Simone Baldi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Hayet Sellami
- Drosophila Research Unit-Parasitology and Mycologie Laboratory, University of Sfax, Sfax 3029, Tunisia
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- SOD of Interdisciplinary Internal Medicine, Careggi University Hospital, Florence 50134, Italy
| | - Leila Keskes
- Laboratory of Human Molecular Genetic, University of Sfax, Sfax 3029, Tunisia
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16
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Cacina C, Ulu E, Arikan S, Surmen ST, Yaylim I. The Investigation of MAPK7 Gene Variations in Colorectal Cancer Risk. In Vivo 2023; 37:644-648. [PMID: 36881097 PMCID: PMC10026633 DOI: 10.21873/invivo.13123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 03/08/2023]
Abstract
BACKGROUND/AIM Mitogen-activated protein kinases (MAPKs) are important regulatory molecules, which have essential roles in physiology and pathology. In the present study, we examined the possible correlation between the MAPK7 gene and colorectal cancer risk in the Turkish population. MATERIALS AND METHODS A total of 100 human DNA samples (50 colorectal cancer patients and 50 healthy individuals) were sequenced using next-generation sequencing to define the potential genetic variations in the MAPK7 gene. RESULTS Five genetic variations (MAPK7; rs2233072, rs2233076, rs181138364, rs34984998, rs148989290) were detected in our study group. The G (variant) allele of the MAPK7; rs2233072 (T>G) gene polymorphism was found in 76% of colorectal cancer cases, and 66% of controls. The prevalence of rs2233076, rs181138364, rs34984998, and rs148989290 gene variations was quite rare in the subjects and no significant association in terms of genotype and allele frequencies was observed between the cases and controls. CONCLUSION No statistically significant correlation between the MAP7 kinase gene variations and colorectal cancer risk was observed. This is the first investigation in the Turkish population that may initiate additional studies in larger populations to analyze the effect of MAPK7 gene on the colorectal cancer risk.
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Affiliation(s)
- Canan Cacina
- Institute of Aziz Sancar Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey;
| | - Elif Ulu
- Institute of Aziz Sancar Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
| | - Soykan Arikan
- Istanbul Education and Research Hospital Surgery Clinic, Istanbul, Turkey
| | - Saime Turan Surmen
- Institute of Aziz Sancar Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
- Department of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Ilhan Yaylim
- Institute of Aziz Sancar Experimental Medicine, Department of Molecular Medicine, Istanbul University, Istanbul, Turkey
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La T, Chen S, Zhao XH, Zhou S, Xu R, Teng L, Zhang YY, Ye K, Xu L, Guo T, Jamaluddin MF, Feng YC, Tang HJ, Wang Y, Xu Q, Gu Y, Cao H, Liu T, Thorne RF, Shao F, Zhang XD, Jin L. LncRNA LIMp27 Regulates the DNA Damage Response through p27 in p53-Defective Cancer Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204599. [PMID: 36638271 PMCID: PMC9982580 DOI: 10.1002/advs.202204599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 12/06/2022] [Indexed: 06/17/2023]
Abstract
P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, this work shows that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover an lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.
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Affiliation(s)
- Ting La
- Translational Research InstituteHenan Provincial and Zhengzhou City Key laboratory of Non‐coding RNA and Cancer MetabolismHenan International Join Laboratory of Non‐coding RNA and Metabolism in CancerHenan Provincial People's HospitalAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450053China
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
- National‐Local Joint Engineering Research Center of Biodiagnosis & BiotherapyThe Second Affiliated HospitalXi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Song Chen
- Translational Research InstituteHenan Provincial and Zhengzhou City Key laboratory of Non‐coding RNA and Cancer MetabolismHenan International Join Laboratory of Non‐coding RNA and Metabolism in CancerHenan Provincial People's HospitalAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450053China
- Institute of Medicinal BiotechnologyJiangsu College of NursingHuai'anJiangsu223300China
| | - Xiao Hong Zhao
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Shuai Zhou
- Translational Research InstituteHenan Provincial and Zhengzhou City Key laboratory of Non‐coding RNA and Cancer MetabolismHenan International Join Laboratory of Non‐coding RNA and Metabolism in CancerHenan Provincial People's HospitalAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450053China
| | - Ran Xu
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Liu Teng
- Translational Research InstituteHenan Provincial and Zhengzhou City Key laboratory of Non‐coding RNA and Cancer MetabolismHenan International Join Laboratory of Non‐coding RNA and Metabolism in CancerHenan Provincial People's HospitalAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450053China
| | - Yuan Yuan Zhang
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Kaihong Ye
- Translational Research InstituteHenan Provincial and Zhengzhou City Key laboratory of Non‐coding RNA and Cancer MetabolismHenan International Join Laboratory of Non‐coding RNA and Metabolism in CancerHenan Provincial People's HospitalAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450053China
| | - Liang Xu
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Tao Guo
- Institute of Future AgricultureNorthwest A&F UniversityYanglingShaanxi712100China
| | - Muhammad Fairuz Jamaluddin
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Yu Chen Feng
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Medicine and Public HealthThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Hai Jie Tang
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Yanliang Wang
- Department of NephrologyHenan Provincial Key Laboratory of Kidney Disease and ImmunologyHenan Provincial Clinical Research Center for Kidney DiseaseHenan Provincial People's HospitalZhengzhouHenan450053China
| | - Qin Xu
- Department of NephrologyHenan Provincial Key Laboratory of Kidney Disease and ImmunologyHenan Provincial Clinical Research Center for Kidney DiseaseHenan Provincial People's HospitalZhengzhouHenan450053China
| | - Yue Gu
- Department of NephrologyHenan Provincial Key Laboratory of Kidney Disease and ImmunologyHenan Provincial Clinical Research Center for Kidney DiseaseHenan Provincial People's HospitalZhengzhouHenan450053China
| | - Huixia Cao
- Department of NephrologyHenan Provincial Key Laboratory of Kidney Disease and ImmunologyHenan Provincial Clinical Research Center for Kidney DiseaseHenan Provincial People's HospitalZhengzhouHenan450053China
| | - Tao Liu
- Children's Cancer Institute Australia for Medical ResearchUniversity of New South WalesSydneyNew South Wales2750Australia
| | - Rick F. Thorne
- Translational Research InstituteHenan Provincial and Zhengzhou City Key laboratory of Non‐coding RNA and Cancer MetabolismHenan International Join Laboratory of Non‐coding RNA and Metabolism in CancerHenan Provincial People's HospitalAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450053China
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Feng‐Min Shao
- Department of NephrologyHenan Provincial Key Laboratory of Kidney Disease and ImmunologyHenan Provincial Clinical Research Center for Kidney DiseaseHenan Provincial People's HospitalZhengzhouHenan450053China
| | - Xu Dong Zhang
- Translational Research InstituteHenan Provincial and Zhengzhou City Key laboratory of Non‐coding RNA and Cancer MetabolismHenan International Join Laboratory of Non‐coding RNA and Metabolism in CancerHenan Provincial People's HospitalAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450053China
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNew South Wales2308Australia
| | - Lei Jin
- Translational Research InstituteHenan Provincial and Zhengzhou City Key laboratory of Non‐coding RNA and Cancer MetabolismHenan International Join Laboratory of Non‐coding RNA and Metabolism in CancerHenan Provincial People's HospitalAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan450053China
- Noncoding Cancer Biomarkers and Therapeutics GroupCancer Detection & Therapy Research ProgramHunter Medical Research InstituteCallaghanNew South Wales2305Australia
- School of Medicine and Public HealthThe University of NewcastleCallaghanNew South Wales2308Australia
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Szász I, Kiss T, Mokánszki A, Koroknai V, Deák J, Patel V, Jámbor K, Ádány R, Balázs M. Identification of liquid biopsy-based mutations in colorectal cancer by targeted sequencing assays. Mol Cell Probes 2023; 67:101888. [PMID: 36513244 DOI: 10.1016/j.mcp.2022.101888] [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: 11/15/2022] [Revised: 12/06/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]
Abstract
Recently, liquid biopsy, as a promising approach was introduced for the analysis of different tumor-derived circulating markers including tumor DNA and cell free DNA (ct/cfDNA). Identification of mutations in cfDNA may allow the early detection of tumors, as well as predicting and monitoring treatment responses in a minimally invasive way. In the present study, we used commercially available gene panels to verify the mutation overlap between liquid biopsy and abnormalities detected in colorectal tumor tissue. The two panels (Archer®VariantPlex®Solid Tumor and LIQUIDPlexTM ctDNA) overlap in 23 genes, which enables a comprehensive view of tumor-plasma mutational status by next generation sequencing. We successfully analyzed 16 plasma and 16 tumor samples. We found that 87% of tumor tissues contained 44 mutations in 12 genes and 43.8% of cfDNA harbored 13 mutations in 5 genes. To verify whether the mutation pattern of the tumor DNA could be consistently detected in plasma cfDNA, we compared the alterations between cfDNA and matched tissue DNA in nine patients. Six of the 9 tumor tissues harbored mutations in TP53, KRAS or MET genes, those were not detectable by the ctDNA kit, even eventhough the exons of these genes overlap in both panels. Comparing the mutational patterns of the matched samples, we found that only one cfDNA had the same mutations (KRAS, SMAD4 and TP53) in the paired tissue. The results of the comparison between tumor tissue DNA and matched plasma cfDNA underline the importance of studying the paired solid tumor and plasma samples together.
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Affiliation(s)
- István Szász
- ELKH-DE Public Health Research Group, University of Debrecen, 4032, Debrecen, Hungary; Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Tímea Kiss
- ELKH-DE Public Health Research Group, University of Debrecen, 4032, Debrecen, Hungary; Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Attila Mokánszki
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Viktória Koroknai
- ELKH-DE Public Health Research Group, University of Debrecen, 4032, Debrecen, Hungary; Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - János Deák
- University of Debrecen Clinical Center, Surgery Clinic, University of Debrecen, Debrecen, Hungary.
| | - Vikas Patel
- Doctoral School of Health Sciences, University of Debrecen, Hungary.
| | - Krisztina Jámbor
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary; Doctoral School of Health Sciences, University of Debrecen, Hungary.
| | - Róza Ádány
- ELKH-DE Public Health Research Group, University of Debrecen, 4032, Debrecen, Hungary; Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
| | - Margit Balázs
- ELKH-DE Public Health Research Group, University of Debrecen, 4032, Debrecen, Hungary; Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary.
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19
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El Hejjioui B, Bouguenouch L, Melhouf MA, El Mouhi H, Bennis S. Clinical Evidence of Circulating Tumor DNA Application in Aggressive Breast Cancer. Diagnostics (Basel) 2023; 13:470. [PMID: 36766575 PMCID: PMC9914403 DOI: 10.3390/diagnostics13030470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 12/28/2022] [Accepted: 01/01/2023] [Indexed: 01/31/2023] Open
Abstract
Breast cancer is clinically and biologically heterogeneous and is classified into different subtypes according to the molecular landscape of the tumor. Triple-negative breast cancer is a subtype associated with higher tumor aggressiveness, poor prognosis, and poor response to treatment. In metastatic breast cancer, approximately 6% to 10% of new breast cancer cases are initially staged IV (de novo metastatic disease). The number of metastatic recurrences is estimated to be 20-30% of all existing breast tumor cases, whereby the need to develop specific genetic markers to improve the prognosis of patients suffering from these deadly forms of breast cancer. As an alternative, liquid biopsy methods can minutely identify the molecular architecture of breast cancer, including aggressive forms, which provides new perspectives for more precise diagnosis and more effective therapeutics. This review aimed to summarize the current clinical evidence for the application of circulating tumor DNA in managing breast cancer by detailing the increased usefulness of this biomarker as a diagnostic, prognostic, monitoring, and surveillance marker for breast cancer.
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Affiliation(s)
- Brahim El Hejjioui
- Biomedical and Translational Research Laboratory, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez 30050, Morocco
- Department of Medical Genetics and Oncogenetics, HASSAN II University Hospital, Fez 30050, Morocco
| | - Laila Bouguenouch
- Department of Medical Genetics and Oncogenetics, HASSAN II University Hospital, Fez 30050, Morocco
| | | | - Hind El Mouhi
- Department of Medical Genetics and Oncogenetics, HASSAN II University Hospital, Fez 30050, Morocco
| | - Sanae Bennis
- Biomedical and Translational Research Laboratory, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez 30050, Morocco
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20
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Lawler T, Su T, Cai Q, Steinwandel MD, Zheng W, Blot WJ, Warren Andersen S. Associations between serum vitamin D biomarkers and tumor expression of Ki67, p53, and COX-2 in colorectal cancer cases from the Southern Community Cohort Study. J Steroid Biochem Mol Biol 2023; 225:106201. [PMID: 36210028 PMCID: PMC9993486 DOI: 10.1016/j.jsbmb.2022.106201] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 09/20/2022] [Accepted: 10/04/2022] [Indexed: 11/15/2022]
Abstract
Higher 25-hydroxyvitamin D is associated with lower colorectal cancer (CRC) risk, with limited data from African Americans (AAs), who have greater risk for CRC and 25-hydroxyvitamin D deficiency. In a predominantly AA sample of CRC cases from the Southern Community Cohort Study (SCCS), we report associations between vitamin D biomarkers and tumor expression of proteins implicated in vitamin D's anti-tumorigenic pathways (e.g. proliferation and inflammation) and CRC prognosis. SCCS participants with incident CRC were identified via state cancer registries. Serum 25-hydroxyvitamin D and vitamin D binding protein (VDBP) were measured at enrollment. 'Free' 25-hydroxyvitamin D was calculated via standard equation. Cellular Ki67, p53, and COX-2 were measured from tumor samples and categorized using literature-defined cut-points related to survival. Generalized linear models were used to measure associations between vitamin D exposures, tumor biomarkers, and stage. In total, 104 cases (40-79 years) were analyzed. 25-hydroxyvitamin D was not associated with high Ki67 (odds ratio (OR) per 1-standard deviation (SD) increase [95% confidence interval] 1.35[0.86-2.11]), p53 (0.75[0.47-1.20]), or COX-2 expression (1.25[0.78-2.01]), or metastatic disease (1.04[0.59-1.81]). Mean biomarker expression was unrelated to 25-hydroxyvitamin D (p-trend ≥.09). Null associations were observed for VDBP and free 25-hydroxyvitamin D. In AAs (n = 70), higher VDBP was associated with lower odds of high Ki67 expression (0.53[0.28-0.98], p-trend =.04). In conclusion, we observed no associations between 25-hydroxyvitamin D and prognostic marker expression in CRC. An inverse association between VDBP and tumor Ki67 in AAs is consistent with reports showing relationships with reduced CRC mortality.
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Affiliation(s)
- Thomas Lawler
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Timothy Su
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Mark D Steinwandel
- International Epidemiology Field Station, Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - William J Blot
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA; International Epidemiology Field Station, Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Shaneda Warren Andersen
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA; School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA.
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21
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The Cytokine Network in Colorectal Cancer: Implications for New Treatment Strategies. Cells 2022; 12:cells12010138. [PMID: 36611932 PMCID: PMC9818504 DOI: 10.3390/cells12010138] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/13/2022] [Accepted: 12/20/2022] [Indexed: 01/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent tumor entities worldwide with only limited therapeutic options. CRC is not only a genetic disease with several mutations in specific oncogenes and/or tumor suppressor genes such as APC, KRAS, PIC3CA, BRAF, SMAD4 or TP53 but also a multifactorial disease including environmental factors. Cancer cells communicate with their environment mostly via soluble factors such as cytokines, chemokines or growth factors to generate a favorable tumor microenvironment (TME). The TME, a heterogeneous population of differentiated and progenitor cells, plays a critical role in regulating tumor development, growth, invasion, metastasis and therapy resistance. In this context, cytokines from cancer cells and cells of the TME influence each other, eliciting an inflammatory milieu that can either enhance or suppress tumor growth and metastasis. Additionally, several lines of evidence exist that the composition of the microbiota regulates inflammatory processes, controlled by cytokine secretion, that play a role in carcinogenesis and tumor progression. In this review, we discuss the cytokine networks between cancer cells and the TME and microbiome in colorectal cancer and the related treatment strategies, with the goal to discuss cytokine-mediated strategies that could overcome the common therapeutic resistance of CRC tumors.
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Kwak AW, Park JW, Lee SO, Lee JY, Seo JH, Yoon G, Lee MH, Choi JS, Shim JH. Isolinderalactone sensitizes oxaliplatin-resistance colorectal cancer cells through JNK/p38 MAPK signaling pathways. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 105:154383. [PMID: 35987016 DOI: 10.1016/j.phymed.2022.154383] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Isolinderalactone (ILL), a sesquiterpene lactone compound, can be extracted from the root of Lindera aggregate. Physiological activities of ILL, including anti-inflammatory and anti-proliferative effects, have been investigated in multiple diseases. Nevertheless, little is known regarding its anti-cancer activities and the mechanism of action of ILL in targeting human CRC cells. PURPOSE To determine ILL-mediated anti-proliferative effects on oxaliplatin (Ox)-sensitive and resistant colorectal cancer (CRC) cells and underlying mechanisms involved in its effects focusing on signal transduction. METHODS Inhibitory effect of ILL on CRC cells was evaluated by analyzing mitochondrial membrane potential (MMP) dysfunction and multi-caspase activity. Apoptosis-regulating proteins and JNK/p38 signaling molecules were monitored by Western blotting. ROS-dependent physiological modifications by ILL were confirmed by pretreatment with N-acetylcysteine (NAC). Moreover, the involvement of JNK/p38 signaling in ROS-mediated apoptosis was verified by treatment with SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor). RESULTS ILL decreased cell viability and colony formation in both CRC Ox-sensitive (HCT116 and HT29) and Ox-resistant (OxR) (HCT116-OxR and HT29-OxR) cells. ILL induced G2/M phase cell cycle arrest, ROS generation, phosphorylated (p)JNK/p38 MAPK activation, mitochondrial membrane potential (MMP) depolarization, and multi-caspase activation, which eventually triggered apoptotic cell death of CRC cells. In addition, combined treatment with ILL and SP600125, SB203580, or pan-caspase inhibitor (Z-VAD-FMK) prevented decreases in cell viability seen after treatment with ILL alone. Pretreatment with NAC attenuated ILL-mediated apoptosis, ROS production, and p-JNK/p38 expression. CONCLUSION Taken together, our results suggest that ILL can exert its anticancer effect in CRC Ox-sensitive and OxR cells by inducing ROS-mediated apoptosis through JNK/p38 MAPK signaling pathways. This is the first study demonstrating that ILL has a potential to improve drug efficacy against resistance mechanisms, providing a new insight into therapeutic strategies targeting drug-resistant CRC.
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Affiliation(s)
- Ah-Won Kwak
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
| | - Jin Woo Park
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea; Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Seung-On Lee
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Jin-Young Lee
- Department of Biological Sciences, Keimyung University, Daegu, 42601, Republic of Korea
| | - Ji-Hye Seo
- Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Goo Yoon
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
| | - Mee-Hyun Lee
- College of Korean Medicine, Dongshin University, Naju, Jeollanam 58245, Republic of Korea
| | - Joon-Seok Choi
- College of Pharmacy, Daegu Catholic University, Gyeongbuk 38430, Korea
| | - Jung-Hyun Shim
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea; Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea; The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, PR China.
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23
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Cyclin-dependent kinases as potential targets for colorectal cancer: past, present and future. Future Med Chem 2022; 14:1087-1105. [PMID: 35703127 DOI: 10.4155/fmc-2022-0064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancer (CRC) is a common cancer in the world and its prevalence is increasing in developing countries. Deregulated cell cycle traverse is a hallmark of malignant transformation and is often observed in CRC as a result of imprecise activity of cell cycle regulatory components, viz. cyclins and cyclin-dependent kinases (CDKs). Apart from cell cycle regulation, some CDKs also regulate processes such as transcription and have also been shown to be involved in colorectal carcinogenesis. This article aims to review cyclin-dependent kinases as potential targets for CRC. Furthermore, therapeutic candidates to target CDKs are also discussed.
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24
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Roesel R, Epistolio S, Molinari F, Saletti P, De Dosso S, Valli M, Franzetti-Pellanda A, Deantonio L, Biggiogero M, Spina P, Popeskou SG, Cristaudi A, Mongelli F, Mazzucchelli L, Stefanini FM, Frattini M, Christoforidis D. A Pilot, Prospective, Observational Study to Investigate the Value of NGS in Liquid Biopsies to Predict Tumor Response After Neoadjuvant Chemo-Radiotherapy in Patients With Locally Advanced Rectal Cancer: The LiBReCa Study. Front Oncol 2022; 12:900945. [PMID: 35837093 PMCID: PMC9274270 DOI: 10.3389/fonc.2022.900945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
IntroductionCirculating tumor DNA (ctDNA) correlates with the response to therapy in different types of cancer. However, in patients with locally advanced rectal cancer (LARC), little is known about how ctDNA levels change with neoadjuvant chemoradiation (Na-ChRT) and how they correlate with treatment response. This work aimed to explore the value of serial liquid biopsies in monitoring response after Na-ChRT with the hypothesis that this could become a reliable biomarker to identify patients with a complete response, candidates for non-operative management.Materials and MethodsTwenty-five consecutive LARC patients undergoing long-term Na-ChRT therapy were included. Applying next-generation sequencing (NGS), we characterized DNA extracted from formalin-fixed paraffin embedded diagnostic biopsy and resection tissue and plasma ctDNA collected at the following time points: the first and last days of radiotherapy (T0, Tend), at 4 (T4), 7 (T7) weeks after radiotherapy, on the day of surgery (Top), and 3–7 days after surgery (Tpost-op). On the day of surgery, a mesenteric vein sample was also collected (TIMV). The relationship between the ctDNA at those time-points and the tumor regression grade (TRG) of the surgical specimen was statistically explored.ResultsWe found no association between the disappearance of ctDNA mutations in plasma samples and pathological complete response (TRG1) as ctDNA was undetectable in the majority of patients from Tend on. However, we observed that the poor (TRG 4) response to Na-ChRT was significantly associated with a positive liquid biopsy at the Top.ConclusionsctDNA evaluation by NGS technology may identify LARC patients with poor response to Na-ChRT. In contrast, this technique does not seem useful for identifying patients prone to developing a complete response.
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Affiliation(s)
- Raffaello Roesel
- Department of Visceral Surgery, Regional Hospital of Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland
- *Correspondence: Raffaello Roesel, ; Samantha Epistolio,
| | - Samantha Epistolio
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
- *Correspondence: Raffaello Roesel, ; Samantha Epistolio,
| | - Francesca Molinari
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Piercarlo Saletti
- Clinical Research Unit, Clinica Luganese Moncucco, Lugano, Switzerland
- Medical Oncology Clinic, Clinica Luganese Moncucco, Lugano, Switzerland
- Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, Switzerland
| | - Sara De Dosso
- Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, Switzerland
- Istituto Oncologico della Svizzera Italiana, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Mariacarla Valli
- Radiation Oncology Clinic, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | | | - Letizia Deantonio
- Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, Switzerland
- Radiation Oncology Clinic, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Maira Biggiogero
- Clinical Research Unit, Clinica Luganese Moncucco, Lugano, Switzerland
| | - Paolo Spina
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
- Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
| | - Sotirios Georgios Popeskou
- Department of Visceral Surgery, Regional Hospital of Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Alessandra Cristaudi
- Department of Visceral Surgery, Regional Hospital of Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Francesco Mongelli
- Department of Visceral Surgery, Regional Hospital of Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Luca Mazzucchelli
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
- Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, Switzerland
| | | | - Milo Frattini
- Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Dimitri Christoforidis
- Department of Visceral Surgery, Regional Hospital of Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland
- Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, Switzerland
- Department of Visceral Surgery, Lausanne University Hospital, Lausanne, Switzerland
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25
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Talaat IM, Yakout NM, Soliman AS, Venkatachalam T, Vinod A, Eldohaji L, Nair V, Hareedy A, Kandil A, Abdel-Rahman WM, Hamoudi R, Saber-Ayad M. Evaluation of Galanin Expression in Colorectal Cancer: An Immunohistochemical and Transcriptomic Study. Front Oncol 2022; 12:877147. [PMID: 35707368 PMCID: PMC9190230 DOI: 10.3389/fonc.2022.877147] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/27/2022] [Indexed: 01/02/2023] Open
Abstract
Colorectal cancer (CRC) represents around 10% of all cancers, with an increasing incidence in the younger age group. The gut is considered a unique organ with its distinctive neuronal supply. The neuropeptide, human galanin, is widely distributed in the colon and expressed in many cancers, including the CRC. The current study aimed to explore the role of galanin at different stages of CRC. Eighty-one CRC cases (TNM stages I - IV) were recruited, and formalin-fixed paraffin-embedded samples were analyzed for the expression of galanin and galanin receptor 1 (GALR1) by immunohistochemistry (IHC). Galanin intensity was significantly lower in stage IV (n= 6) in comparison to other stages (p= 0.037 using the Mann-Whitney U test). Whole transcriptomics analysis using NGS was performed for selected samples based on the galanin expression by IHC [early (n=5) with high galanin expression and late (n=6) with low galanin expression]. Five differentially regulated pathways (using Absolute GSEA) were identified as drivers for tumor progression and associated with higher galanin expression, namely, cell cycle, cell division, autophagy, transcriptional regulation of TP53, and immune system process. The top shared genes among the upregulated pathways are AURKA, BIRC5, CCNA1, CCNA2, CDC25C, CDK2, CDK6, EREG, LIG3, PIN1, TGFB1, TPX2. The results were validated using real-time PCR carried out on four cell lines [two primaries (HCT116 and HT29) and two metastatic (LoVo and SK-Co-1)]. The current study shows galanin as a potential negative biomarker. Galanin downregulation is correlated with advanced CRC staging and linked to cell cycle and division, autophagy, transcriptional regulation of TP53 and immune system response.
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Affiliation(s)
- Iman M. Talaat
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Nada M. Yakout
- Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | | | - Thenmozhi Venkatachalam
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Physiology and Immunology, College of Medicine and Health Science, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Arya Vinod
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Leen Eldohaji
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Vidhya Nair
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Amal Hareedy
- Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Alaa Kandil
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Alexandria University, Cairo, Egypt
| | - Wael M. Abdel-Rahman
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Rifat Hamoudi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London, United Kingdom
| | - Maha Saber-Ayad
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Pharmacology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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26
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Ding L, Zhao C, Xu Y, Zhang Z, Nie Y, Liao K, Chen Y, Tu B, Zhang X. Mutations in DNA binding domain of p53 impede RSL1D1-p53 interaction to escape from degradation in human colorectal cancer cells. Exp Cell Res 2022; 417:113211. [PMID: 35597299 DOI: 10.1016/j.yexcr.2022.113211] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/11/2022] [Accepted: 05/14/2022] [Indexed: 02/07/2023]
Abstract
Different from the nucleolus-specific localization in some types of cancer cells, ribosomal L1 domain-containing protein 1 (RSL1D1) distributes throughout the nucleus in human colorectal cancer (CRC) cells. RSL1D1 directly interacts with DNA binding domain (aa 93-292) of wild-type p53 (p53-WT) and thereby recruits p53 to HDM2. The ensuing formation of RSL1D1/HDM2/p53 complex enhances p53 ubiquitination and decreases the protein level of p53 in CRC cells. In this study, we investigated the interaction between RSL1D1 and mutant p53 proteins. We first corroborated that aa 93-224 of p53 is a more precise domain for RSL1D1 binding and mutation in either aa 93-224 or aa 225-292 domain of p53 affects RSL1D1-p53 interaction. R175H mutated p53 does not interact with RSL1D1, whereas R273H mutated p53 still can bind to RSL1D1 but showing a remarkably decreased affinity than p53-WT. Although p53-R273H retained a weakened binding affinity with RSL1D1, it can hardly be recruited to HDM2 by RSL1D1 in HCT116 CRC cells. Accordingly, RSL1D1 lost its capacity to negatively regulate either R175H or R273H p53 mutant via directly interaction in HCT116 cells, thereby facilitating p53 mutants to accumulate and gain oncogenic function. Our findings help explain why mutant p53 proteins are more stable than p53-WT in CRC cells.
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Affiliation(s)
- Li Ding
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China
| | - Chenhong Zhao
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China
| | - Yujie Xu
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China
| | - Zhiping Zhang
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China
| | - Yesen Nie
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China
| | - Kai Liao
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China
| | - Yuerou Chen
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China
| | - Beibei Tu
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China
| | - Xinyue Zhang
- College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, 225009, China; Joint International Research Laboratory of Agriculture & Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, 225009, China; Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, The Ministry of Agriculture of China, Yangzhou University (26116120), Yangzhou, Jiangsu, 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, 225009, China.
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27
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Zitkute V, Kukcinaviciute E, Jonusiene V, Starkuviene V, Sasnauskiene A. Differential effects of 5‐fluorouracil and oxaliplatin on autophagy in chemoresistant colorectal cancer cells. J Cell Biochem 2022; 123:1103-1115. [DOI: 10.1002/jcb.30267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 03/30/2022] [Accepted: 04/20/2022] [Indexed: 12/22/2022]
Affiliation(s)
- Vilmante Zitkute
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
| | - Egle Kukcinaviciute
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
| | - Violeta Jonusiene
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
| | - Vytaute Starkuviene
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
- BioQuant Heidelberg University Heidelberg Germany
| | - Ausra Sasnauskiene
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center Vilnius University Vilnius Lithuania
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Zhao L, Chen H, Zhang Q, Ma J, Hu H, Xu L. ATF4-mediated microRNA-145/HDAC4/p53 axis affects resistance of colorectal cancer cells to 5-fluorouracil by regulating autophagy. Cancer Chemother Pharmacol 2022; 89:595-607. [PMID: 35312836 DOI: 10.1007/s00280-021-04393-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 12/21/2021] [Indexed: 01/07/2023]
Abstract
BACKGROUND The impact of activating transcription factor 4 (ATF4), differentially expressed in colorectal cancer (CRC), on 5-Fluorouracil (5-FU) chemoresistance has not been fully explained. The purpose of this study is to evaluate the clinical significance of ATF4-mediated microRNA-145 (miR-145)/histone deacetylase 4 (HDAC4)/p53 axis in CRC. METHODS Initially, the expression of ATF4, miR-145, HDAC4, and p53 in CRC tissues and cells was quantified by RT-qPCR and immunoblotting. Next, luciferase activity and chromatin immunoprecipitation assays were performed to verify the binding affinity among miR-145, ATF4, and HDAC4. Moreover, proliferation, clone formation, and apoptosis in CRC cells treated with 5-FU were assessed after gain- or loss-of-function of ATF4, miR-145, and/or HDAC4. Furthermore, the tumorigenicity and chemoresistance of CRC cells in mice were assayed for validating the in vitro findings. RESULTS ATF4 and HDAC4 were highly expressed, while miR-145 and p53 were poorly expressed in CRC tissues and cells. miR-145 targeted and negatively regulated HDAC4 to activate p53, and miR-145 expression was suppressed by ATF4. Of note, ATF4 facilitated cell proliferation and clone formation ability and repressed apoptosis to promote autophagy and chemoresistance of CRC cells by regulating the miR-145/HDAC4/p53 axis. In vivo experiment elucidated that ATF4-mediated miR-145/HDAC4/p53 axis enhanced tumorigenesis and resistance of CRC cells to 5-FU. CONCLUSION In conclusion, ATF4-mediated miR-145 inhibition accelerated autophagy of CRC cells and boosted their resistance to 5-FU via the HDAC4/p53 axis.
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Affiliation(s)
- Lin Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, 215006, Jiangsu, China
- Department of General Surgery, Mudanjiang First People's Hospital, Mudanjiang, 157011, China
| | - Hong Chen
- Department of General Surgery, Suzhou Dushu Lake Hospital Affiliated to Soochow University, Suzhou, 215000, China
| | - QingYi Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, 215006, Jiangsu, China
| | - Jin Ma
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, 215006, Jiangsu, China
| | - Hao Hu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, 215006, Jiangsu, China.
| | - Lu Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, 215006, Jiangsu, China.
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Liu S, Yu J, Zhang H, Liu J. TP53 Co-Mutations in Advanced EGFR-Mutated Non-Small Cell Lung Cancer: Prognosis and Therapeutic Strategy for Cancer Therapy. Front Oncol 2022; 12:860563. [PMID: 35444951 PMCID: PMC9013831 DOI: 10.3389/fonc.2022.860563] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 03/16/2022] [Indexed: 12/25/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. As the most prevalent molecular mutation subtypes in non-small cell lung cancer (NSCLC), EGFR-TKIs are currently a standard first-line therapy for targeting the mutated EGFR in advanced NSCLC patients. However, 20-30% of this subset of patients shows primary resistance to EGFR-TKIs. Patients with co-mutations of EGFR and several other genes have a poor response to EGFR-TKIs, whereas the prognostic and predictive significance of EGFR/TP53 co-mutation in NSCLC patients remains controversial. Meanwhile, little is known about how to choose an optimal therapeutic strategy for this subset of patients. Presently, no drugs targeting TP53 mutations are available on the market, and some p53 protein activators are in the early stage of clinical trials. A combination of EGFR-TKIs with antiangiogenic agents or chemotherapy or other agents might be a more appropriate strategy to tackle the problem. In this review, we describe the prognostic and predictive value of EGFR/TP53 co-mutation in NSCLC patients, investigate the mechanisms of this co-mutation affecting the response to EGFR-TKIs, and further explore optimal regimens effectively to prolong the survival time of the NSCLC patients harboring this co-mutation.
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Affiliation(s)
- Surui Liu
- Department of Oncology, Jinan Central Hospital, Jinan, China.,Department of Oncology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Jin Yu
- Department of Oncology, Jinan Central Hospital, Jinan, China
| | - Hui Zhang
- Department of Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jie Liu
- Department of Oncology, Jinan Central Hospital, Jinan, China
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30
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Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer. Biomolecules 2022; 12:biom12040548. [PMID: 35454137 PMCID: PMC9029346 DOI: 10.3390/biom12040548] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/28/2022] [Accepted: 03/06/2022] [Indexed: 02/07/2023] Open
Abstract
TP53 is a tumor suppressor gene that encodes a sequence-specific DNA-binding transcription factor activated by stressful stimuli; it upregulates target genes involved in growth suppression, cell death, DNA repair, metabolism, among others. TP53 is the most frequently mutated gene in tumors, with mutations not only leading to loss-of-function (LOF), but also gain-of-function (GOF) that promotes tumor progression, and metastasis. The tumor-specific status of mutant p53 protein has suggested it is a promising target for cancer therapy. We summarize the current progress of targeting wild-type and mutant p53 for cancer therapy through biotherapeutic and biopharmaceutical methods for (1) boosting p53 activity in cancer, (2) p53-dependent and p53-independent strategies for targeting p53 pathway functional restoration in p53-mutated cancer, (3) targeting p53 in immunotherapy, and (4) combination therapies targeting p53, p53 checkpoints, or mutant p53 for cancer therapy.
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31
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Mayer M, Berger A, Leischner C, Renner O, Burkard M, Böcker A, Noor S, Weiland T, Weiss TS, Busch C, Lauer UM, Bischoff SC, Venturelli S. Preclinical Efficacy and Toxicity Analysis of the Pan-Histone Deacetylase Inhibitor Gossypol for the Therapy of Colorectal Cancer or Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2022; 15:ph15040438. [PMID: 35455435 PMCID: PMC9028974 DOI: 10.3390/ph15040438] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/17/2022] [Accepted: 03/30/2022] [Indexed: 11/18/2022] Open
Abstract
Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5–50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity.
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Affiliation(s)
- Mascha Mayer
- Institute of Nutritional Medicine and Prevention, University of Hohenheim, 70599 Stuttgart, Germany;
| | - Alexander Berger
- Department of Internal Medicine VIII, University Hospital Tuebingen, 72076 Tuebingen, Germany; (A.B.); (T.W.); (U.M.L.)
| | - Christian Leischner
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, 70599 Stuttgart, Germany; (C.L.); (O.R.); (M.B.)
| | - Olga Renner
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, 70599 Stuttgart, Germany; (C.L.); (O.R.); (M.B.)
| | - Markus Burkard
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, 70599 Stuttgart, Germany; (C.L.); (O.R.); (M.B.)
| | | | - Seema Noor
- Department of Dermatology, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany;
| | - Timo Weiland
- Department of Internal Medicine VIII, University Hospital Tuebingen, 72076 Tuebingen, Germany; (A.B.); (T.W.); (U.M.L.)
| | - Thomas S. Weiss
- Center for Liver Cell Research, Children’s University Hospital (KUNO), University Hospital Regensburg, 93042 Regensburg, Germany;
| | | | - Ulrich M. Lauer
- Department of Internal Medicine VIII, University Hospital Tuebingen, 72076 Tuebingen, Germany; (A.B.); (T.W.); (U.M.L.)
- German Cancer Consortium (DKTK), DKFZ Partner Site, 72076 Tuebingen, Germany
| | - Stephan C. Bischoff
- Institute of Nutritional Medicine and Prevention, University of Hohenheim, 70599 Stuttgart, Germany;
- Correspondence: (S.C.B.); (S.V.); Tel.: +49-711-459-24100 (S.C.B.); +49-711-459-24195 (S.V.)
| | - Sascha Venturelli
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, 70599 Stuttgart, Germany; (C.L.); (O.R.); (M.B.)
- Department of Vegetative and Clinical Physiology, Institute of Physiology, University of Tuebingen, 72074 Tuebingen, Germany
- Correspondence: (S.C.B.); (S.V.); Tel.: +49-711-459-24100 (S.C.B.); +49-711-459-24195 (S.V.)
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32
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Sun Y, Liu B, Chen Y, Xing Y, Zhang Y. Multi-Omics Prognostic Signatures Based on Lipid Metabolism for Colorectal Cancer. Front Cell Dev Biol 2022; 9:811957. [PMID: 35223868 PMCID: PMC8874334 DOI: 10.3389/fcell.2021.811957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022] Open
Abstract
Background: The potential biological processes and laws of the biological components in malignant tumors can be understood more systematically and comprehensively through multi-omics analysis. This study elaborately explored the role of lipid metabolism in the prognosis of colorectal cancer (CRC) from the metabonomics and transcriptomics. Methods: We performed K-means unsupervised clustering algorithm and t test to identify the differential lipid metabolites determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in the serum of 236 CRC patients of the First Hospital of Jilin University (JLUFH). Cox regression analysis was used to identify prognosis-associated lipid metabolites and to construct multi-lipid-metabolite prognostic signature. The composite nomogram composed of independent prognostic factors was utilized to individually predict the outcome of CRC patients. Glycerophospholipid metabolism was the most significant enrichment pathway for lipid metabolites in CRC, whose related hub genes (GMRHGs) were distinguished by gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis were utilized to develop the prognostic signature. Results: Six-lipid-metabolite and five-GMRHG prognostic signatures were developed, indicating favorable survival stratification effects on CRC patients. Using the independent prognostic factors as variables, we established a composite nomogram to individually evaluate the prognosis of CRC patients. The AUCs of one-, three-, and five-year ROC curves were 0.815, 0.815, and 0.805, respectively, showing auspicious prognostic accuracy. Furthermore, we explored the potential relationship between tumor microenvironment (TME) and immune infiltration. Moreover, the mutational frequency of TP53 in the high-risk group was significantly higher than that in the low-risk group (p < 0.001), while in the coordinate mutational status of TP53, the overall survival of CRC patients in the high-risk group was significantly lower than that in low-risk group with statistical differences. Conclusion: We identified the significance of lipid metabolism for the prognosis of CRC from the aspects of metabonomics and transcriptomics, which can provide a novel perspective for promoting individualized treatment and revealing the potential molecular biological characteristics of CRC. The composite nomogram including a six-lipid-metabolite prognostic signature is a promising predictor of the prognosis of CRC patients.
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Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis. Cancers (Basel) 2022; 14:cancers14010219. [PMID: 35008383 PMCID: PMC8750794 DOI: 10.3390/cancers14010219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/23/2021] [Accepted: 12/30/2021] [Indexed: 02/05/2023] Open
Abstract
The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors.
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34
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Hasbullah HH, Musa M. Gene Therapy Targeting p53 and KRAS for Colorectal Cancer Treatment: A Myth or the Way Forward? Int J Mol Sci 2021; 22:11941. [PMID: 34769370 PMCID: PMC8584926 DOI: 10.3390/ijms222111941] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and is responsible as one of the main causes of mortality in both men and women. Despite massive efforts to raise public awareness on early screening and significant advancements in the treatment for CRC, the majority of cases are still being diagnosed at the advanced stage. This contributes to low survivability due to this cancer. CRC patients present various genetic changes and epigenetic modifications. The most common genetic alterations associated with CRC are p53 and KRAS mutations. Gene therapy targeting defect genes such as TP53 (tumor suppressor gene encodes for p53) and KRAS (oncogene) in CRC potentially serves as an alternative treatment avenue for the disease in addition to the standard therapy. For the last decade, significant developments have been seen in gene therapy for translational purposes in treating various cancers. This includes the development of vectors as delivery vehicles. Despite the optimism revolving around targeted gene therapy for cancer treatment, it also has various limitations, such as a lack of availability of related technology, high cost of the involved procedures, and ethical issues. This article will provide a review on the potentials and challenges of gene therapy targeting p53 and KRAS for the treatment of CRC.
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Affiliation(s)
| | - Marahaini Musa
- Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
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35
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Shi J, Bao M, Wang W, Wu X, Li Y, Zhao C, Liu W. Integrated Profiling Identifies PLOD3 as a Potential Prognostic and Immunotherapy Relevant Biomarker in Colorectal Cancer. Front Immunol 2021; 12:722807. [PMID: 34646265 PMCID: PMC8503557 DOI: 10.3389/fimmu.2021.722807] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/08/2021] [Indexed: 12/12/2022] Open
Abstract
Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 3 (PLOD3) is related to a variety of human diseases. However, its function in Colorectal cancer (CRC) remains uncertain. PLOD3 expression was analyzed using The Cancer Genome Atlas (TCGA) pan-cancer data. DAVID was used for enrichment analysis of PLOD3-related genes. The correlation between PLOD3 expression and immune cell infiltration was evaluated. Four expression profile datasets (GSE17536, GSE39582, GSE74602, and GSE113513) from Gene Expression Omnibus, and two proteomic datasets were used as validation cohorts for assessing the diagnostic and prognostic value of PLOD3 in CRC. What's more, we performed immunohistochemistry (IHC) staining for PLOD3 in 160 paired CRC specimens and corresponding adjacent non-tumor tissues. PLOD3 was highly expressed in many tumors including CRC. PLOD3 was upregulated in advanced stage CRCs, and high PLOD3 expression was associated with poor survival. High PLOD3 expression was associated with low levels of B cells, CD4+ T cells, M1 macrophages, CD8+ T cells, and multiple immunerelated characteristics. In addition, the high PLOD3 expression group had a higher TIDE score and a lower tumor mutation burden and microsatellite instability, indicating that patients with high PLOD3 expression may be resistant to immunotherapy. Additional datasets and IHC analysis were used to validate the diagnostic and prognostic value of PLOD3 at the mRNA and protein levels in CRC. Patients with non-response to immunotherapy showed increased PLOD3 expression in an immunotherapy treated dataset. PLOD3 is a potential biomarker for CRC diagnosis and prognosis prediction. CRCs with high PLOD3 expression may be resistant to immune checkpoint therapy.
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Affiliation(s)
- Junhong Shi
- Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Meiyu Bao
- Department of Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Weifeng Wang
- Department of Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Xuan Wu
- Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yueying Li
- Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Changdong Zhao
- Department of Gastroenterology, Second People's Hospital of Lianyungang City, Lianyungang, China
| | - Weiwei Liu
- Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
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36
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Carlsen L, Schorl C, Huntington K, Hernandez-Borrero L, Jhaveri A, Zhang S, Zhou L, El-Deiry WS. Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells. Oncotarget 2021; 12:2006-2021. [PMID: 34611476 PMCID: PMC8487728 DOI: 10.18632/oncotarget.28075] [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: 08/02/2021] [Accepted: 08/28/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53-/- colorectal cancer cells treated with these drugs and report pan-drug, drug-specific, drug class-specific, p53-independent, and p53-dependent signatures. We observed downregulation of histone genes by 5-FU (that significantly correlates with improved survival in CRC patients) and upregulation of FOS and ATF3 by oxaliplatin (which may contribute to peripheral neuropathy). BTG2 was identified as a top gene upregulated by all four drugs, suggesting its critical role in the cellular response to chemotherapy in CRC. Soluble TRAILR2 (death receptor 5; DR5) is a decoy receptor for TRAIL, an apoptosis-inducing cytokine. TRAILR2 was down-regulated by oxaliplatin and 5-FU, was not affected by CPT-11, and was increased by cisplatin. There was an increase in IL-8 by oxaliplatin and increase in ferritin by cisplatin which may contribute to cancer cell survival. Novel drug-specific mechanisms of efficacy or toxicity identified in these signatures may be targeted with combination therapies or development of new targeted therapies. Together, the findings here contribute to our understanding of the molecular bases of efficacy and toxicity of chemotherapeutic agents often used for treatment of GI cancer such as CRC.
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Affiliation(s)
- Lindsey Carlsen
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI 02903, USA.,Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Pathobiology Graduate Program, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Christoph Schorl
- The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI 02903, USA.,Department of Molecular Biology, Cell Biology and Biochemistry, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Genomics Core Facility, Brown University, Providence, RI 02903, USA.,Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Kelsey Huntington
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI 02903, USA.,Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Pathobiology Graduate Program, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Liz Hernandez-Borrero
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI 02903, USA.,Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Pathobiology Graduate Program, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Aakash Jhaveri
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Shengliang Zhang
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI 02903, USA.,Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Lanlan Zhou
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI 02903, USA.,Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI 02903, USA.,Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Pathobiology Graduate Program, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.,Hematology-Oncology Division, Department of Medicine, Rhode Island Hospital and Brown University, Providence, RI 02903, USA.,Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
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Postoperative Circulating Tumor DNA Can Predict High Risk Patients with Colorectal Cancer Based on Next-Generation Sequencing. Cancers (Basel) 2021; 13:cancers13164190. [PMID: 34439344 PMCID: PMC8391973 DOI: 10.3390/cancers13164190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/16/2021] [Accepted: 08/19/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Circulating tumor DNA (ctDNA) is a minimally invasive biomarker useful for monitoring minimum residual disease, recurrence, and treatment response in colorectal cancer (CRC). We analyzed circulating tumor DNA from patients with CRC to evaluate analytical and clinical performances using next-generation sequencing (NGS). It is clear that postoperative circulating tumor DNA detection provides valuable information to determine whether a patient might at high risk of disease recurrence or have a persistent tumor lesion. The NGS assay not only showed excellent analytical performance, but also shows a state-of-art diagnostic option in patient-oriented precision medicine. Abstract The objective of this study was to characterize circulating tumor DNA (ctDNA) mutations in colorectal cancer (CRC) patients and evaluate their prognostic values during treatment. Forty-nine patients with CRC planned for operation were enrolled. A total of 115 plasma samples were collected pre-operation, post-operation, and post-chemotherapy. ctDNA analysis was performed using next-generation sequencing (NGS) including 14 genes. In 22 (44.9%) out of 49 patients, at least one mutation (40 total mutations) was detected in the initial plasma sample. The median sum of variant allele frequency was 0.74% (range: 0.10–29.57%). TP53 mutations were the most frequent (17 of 49 patients, 34.7%), followed by APC (18.4%), KRAS (12.2%), FBXW7 (8.2%), NRAS (2.0%), PIK3CA (2.0%), and SMAD4 (2.0%). After surgery, five (14.3%) out of 35 patients harbored ctDNA mutation. All five patients experienced relapse or metastasis during follow-up. It was noteworthy that all three patients with persistent ctDNA relapsed after R0 resection. After chemotherapy, ctDNA analysis was performed for 31 patients, all of which were ctDNA-negative. Analytical and clinical performances of NGS to utilize ctDNA in CRC were determined. Results revealed that postoperative ctDNA might serve as a marker for identifying risk of recurrence, thus contributing to patient-oriented treatment strategies.
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Park SS, Ryu YS, Koh DI, Hong SW, Moon JH, Shin JS, Kim MJ, Kim DY, Hong JK, Kim EH, Jeong HR, Park YS, Kim J, Kim DM, Yun H, Shin JY, Jin DH. Mutation SVCT2 promotes cell proliferation, invasion and migration in colorectal cancer. J Cancer 2021; 12:5385-5393. [PMID: 34405001 PMCID: PMC8364649 DOI: 10.7150/jca.57463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 06/04/2021] [Indexed: 12/24/2022] Open
Abstract
The sodium-dependent vitamin C transporter 2 (SVCT2) surface glycoprotein regulates ascorbate accumulation in the plasma, often resulting in the induction of cancer cell death. Therefore, high expression of this gene associates with increased overall survival in several cancers. However, in colorectal cancer (CRC), high (likely mutated) SVCT2 expression relates to poor overall survival, and its functional significance has not been studied. Thus, we hypothesize that mutant SVCT2 expression could affect CRC patient survival. According to biological databases, SVCT2 has been found to be mutated frequently, and SVCT2 E264K has a particularly high pathogenic score (0.98), compared to other SVCT2 mutant sites, in CRC patients. Interestingly, our results reveal expression of SVCT2 E264K in many CRC tissues and cells. Also, we found wild-type SVCT2 expression to be largely localized to the cytoplasm and membrane, while SVCT2 E264K was restricted to the cytoplasm. We further found that SVCT2 E264K overexpression increases cell growth. By contrast, SVCT2 E264K knockdown significantly reduced cell proliferation and promoted cell apoptosis, resulting in inhibition of cell invasion and migration. Taken together, SVCT2 E264K plays a critical role in proliferation in CRC. Our results suggest that SVCT2 E264K could be a promising novel therapeutic target in CRC.
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Affiliation(s)
- Sang-Soo Park
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yea Seong Ryu
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-In Koh
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Seung-Woo Hong
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Jai-Hee Moon
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Jae-Sik Shin
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Mi Jin Kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Do Yeon Kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jun Ki Hong
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun Ho Kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hong-Rae Jeong
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yoon Sun Park
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joseph Kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong Min Kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyeseon Yun
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joo-Yeon Shin
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-Hoon Jin
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Kong X, Yu D, Wang Z, Li S. Relationship between p53 status and the bioeffect of ionizing radiation. Oncol Lett 2021; 22:661. [PMID: 34386083 PMCID: PMC8299044 DOI: 10.3892/ol.2021.12922] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 06/30/2021] [Indexed: 12/11/2022] Open
Abstract
Radiotherapy is widely used in the clinical treatment of cancer patients and it may be used alone or in combination with surgery or chemotherapy to inhibit tumor development. However, radiotherapy may at times not kill all cancer cells completely, as certain cells may develop radioresistance that counteracts the effects of radiation. The emergence of radioresistance is associated with the genetic background and epigenetic regulation of cells. p53 is an important tumor suppressor gene that is expressed at low levels in cells. However, when cells are subjected to stress-induced stimulation, the expression level of p53 increases, thereby preventing genomic disruption. This mechanism has important roles in maintaining cell stability and inhibiting carcinogenesis. However, mutation and deletion destroy the anticancer function of p53 and may induce carcinogenesis. In tumor radiotherapy, the status of p53 expression in cancer cells has a close relationship with radiotherapeutic efficacy. Therefore, understanding how p53 expression affects the cellular response to radiation is of great significance for solving the problem of radioresistance and improving radiotherapeutic outcomes. For the present review, the literature was searched for studies published between 1979 and 2021 using the PubMed database (https://pubmed.ncbi.nlm.nih.gov/) with the following key words: Wild-type p53, mutant-type p53, long non-coding RNA, microRNA, gene mutation, radioresistance and radiosensitivity. From the relevant studies retrieved, the association between different p53 mutants and cellular radiosensitivity, as well as the molecular mechanisms of p53 affecting the radiosensitivity of cells, were summarized. The aim of the present study was to provide useful information for understanding and resolving radioresistance, to help clinical researchers develop more accurate treatment strategies and to improve radiotherapeutic outcomes for cancer patients with p53 mutations.
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Affiliation(s)
- Xiaohan Kong
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Dehai Yu
- Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, Jilin 130061, P.R. China
| | - Zhaoyi Wang
- Department of Gastrointestinal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Sijie Li
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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40
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Su H, Qin M, Liu Q, Jin B, Shi X, Xiang Z. Ubiquitin-Like Protein UBD Promotes Cell Proliferation in Colorectal Cancer by Facilitating p53 Degradation. Front Oncol 2021; 11:691347. [PMID: 34350116 PMCID: PMC8327751 DOI: 10.3389/fonc.2021.691347] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 06/30/2021] [Indexed: 11/25/2022] Open
Abstract
Purpose Ubiquitin D (UBD) is a member of the ubiquitin-like modifier (UBL) family and is highly expressed in a variety of cancers including colorectal cancer (CRC). However, the mechanisms of its regulatory roles in CRC are largely elusive. In this study, we revealed the effect of UBD on the proliferation of CRC. Methods The expression of UBD in clinical tissue samples of CRC and seven CRC cell lines was detected using qRT-PCR, immunohistochemistry (IHC) and Western blotting. CCK-8, colony formation, EdU and flow cytometry assays were used to detect the functional changes of CRC cells transfected with UBD stable expression plasmids in vitro. A xenograft model was constructed to assess the effect of UBD on the growth of CRC cells in vivo. The connection between UBD and p53 was analyzed using Western blotting, immunoprecipitation, proteasome inhibition assay and Cycloheximide (CHX) chase assay. Results UBD was overexpressed in CRC tumor tissues compared with nontumor tissues, and its overexpression was positively associated with the tumor size and TNM stage of CRC patients. Functionally, UBD significantly accelerated CRC cell viability and proliferation in vitro and promoted tumorigenesis in vivo. Mechanistically, UBD interacted with p53 in CRC cells, downregulated the expression of p53 by regulating its degradation, shortened the p53 half-life, thereby further affecting the decrease in p21 and the increase in Cyclin D1, Cyclin E, CDK2, CDK4 and CDK6. Moreover, in vivo experiments showed that UBD-induced tumor growth in nude mice was dependent on a decrease in p53. Conclusions Our study proved that UBD mediates the degradation of p53, thereby facilitating the growth of CRC cells and ultimately promoting the progression of CRC. Therefore, UBD may be a potential therapeutic target and a promising prognostic biomarker for CRC.
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Affiliation(s)
- Hongbin Su
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mengdi Qin
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiang Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Jin
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xianjun Shi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zheng Xiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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41
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Inoue A, Robinson FS, Minelli R, Tomihara H, Rizi BS, Rose JL, Kodama T, Srinivasan S, Harris AL, Zuniga AM, Mullinax RA, Ma X, Seth S, Daniele JR, Peoples MD, Loponte S, Akdemir KC, Khor TO, Feng N, Roszik J, Sobieski MM, Brunell D, Stephan C, Giuliani V, Deem AK, Shingu T, Deribe YL, Menter DG, Heffernan TP, Viale A, Bristow CA, Kopetz S, Draetta GF, Genovese G, Carugo A. Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer. Gastroenterology 2021; 161:196-210. [PMID: 33745946 PMCID: PMC8238881 DOI: 10.1053/j.gastro.2021.03.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 02/24/2021] [Accepted: 03/05/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer. METHODS To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC. RESULTS Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC. CONCLUSIONS Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.
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Affiliation(s)
- Akira Inoue
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan.
| | - Frederick S Robinson
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rosalba Minelli
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hideo Tomihara
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bahar Salimian Rizi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Johnathon L Rose
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Sanjana Srinivasan
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Angela L Harris
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andy M Zuniga
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert A Mullinax
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaoyan Ma
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sahil Seth
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Joseph R Daniele
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael D Peoples
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sara Loponte
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kadir C Akdemir
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tin Oo Khor
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ningping Feng
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jason Roszik
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mary M Sobieski
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - David Brunell
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - Clifford Stephan
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas
| | - Virginia Giuliani
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Angela K Deem
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Takashi Shingu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yonathan Lissanu Deribe
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Timothy P Heffernan
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andrea Viale
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christopher A Bristow
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Giulio F Draetta
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Giannicola Genovese
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Alessandro Carugo
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Welsh M. The Felicitous Success of the Subsection Molecular Oncology of International Journal of Molecular Sciences. Int J Mol Sci 2021; 22:ijms22136939. [PMID: 34203257 PMCID: PMC8268909 DOI: 10.3390/ijms22136939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 11/25/2022] Open
Abstract
The evolvement of the newly started subsection IJMS molecular oncology is discussed. The breadth and depth of the journal articles is alluded to. A bright future for this subsection is anticipated, developing into a top tier cancer journal.
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Affiliation(s)
- Michael Welsh
- Department of Medical Cell Biology, Uppsala University, Husargatan 3, P.O. Box 571, 75123 Uppsala, Sweden
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Mazouji O, Ouhajjou A, Incitti R, Mansour H. Updates on Clinical Use of Liquid Biopsy in Colorectal Cancer Screening, Diagnosis, Follow-Up, and Treatment Guidance. Front Cell Dev Biol 2021; 9:660924. [PMID: 34150757 PMCID: PMC8213391 DOI: 10.3389/fcell.2021.660924] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, being the third most diagnosed in the world and the second deadliest. Solid biopsy provides an essential guide for the clinical management of patients with colorectal cancer; however, this method presents several limitations, in particular invasiveness, and cannot be used repeatedly. Recently, clinical research directed toward the use of liquid biopsy, as an alternative tool to solid biopsy, showed significant promise in several CRC clinical applications, as (1) detect CRC patients at early stage, (2) make treatment decision, (3) monitor treatment response, (4) predict relapses and metastases, (5) unravel tumor heterogeneity, and (6) detect minimal residual disease. The purpose of this short review is to describe the concept, the characteristics, the genetic components, and the technologies used in liquid biopsy in the context of the management of colorectal cancer, and finally we reviewed gene alterations, recently described in the literature, as promising potential biomarkers that may be specifically used in liquid biopsy tests.
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Affiliation(s)
- Omayma Mazouji
- GES-LCM2E, FPN, Mohamed First University, Oujda, Morocco
| | | | - Roberto Incitti
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Hicham Mansour
- GES-LCM2E, FPN, Mohamed First University, Oujda, Morocco
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Meng M, Zhong K, Jiang T, Liu Z, Kwan HY, Su T. The current understanding on the impact of KRAS on colorectal cancer. Biomed Pharmacother 2021; 140:111717. [PMID: 34044280 DOI: 10.1016/j.biopha.2021.111717] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
KRAS (kirsten rat sarcoma viral oncogene) is a member of the RAS family. KRAS mutations are one of most dominant mutations in colorectal cancer (CRC). The impact of KRAS mutations on the prognosis and survival of CRC patients drives many research studies to explore potential therapeutics or target therapy for the KRAS mutant CRC. This review summarizes the current understanding of the pathological consequences of the KRAS mutations in the development of CRC; and the impact of the mutations on the response and the sensitivity to the current front-line chemotherapy. The current therapeutic strategies for treating KRAS mutant CRC, the difficulties and challenges will also be discussed.
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Affiliation(s)
- Mingjing Meng
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Keying Zhong
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ting Jiang
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhongqiu Liu
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Hiu Yee Kwan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Tao Su
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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Basnet U, Patil AR, Kulkarni A, Roy S. Role of Stress-Survival Pathways and Transcriptomic Alterations in Progression of Colorectal Cancer: A Health Disparities Perspective. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:5525. [PMID: 34063993 PMCID: PMC8196775 DOI: 10.3390/ijerph18115525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/07/2021] [Accepted: 05/19/2021] [Indexed: 12/09/2022]
Abstract
Every year, more than a million individuals are diagnosed with colorectal cancer (CRC) across the world. Certain lifestyle and genetic factors are known to drive the high incidence and mortality rates in some groups of individuals. The presence of enormous amounts of reactive oxygen species is implicated for the on-set and carcinogenesis, and oxidant scavengers are thought to be important in CRC therapy. In this review, we focus on the ethnicity-based CRC disparities in the U.S., the negative effects of oxidative stress and apoptosis, and gene regulation in CRC carcinogenesis. We also highlight the use of antioxidants for CRC treatment, along with screening for certain regulatory genetic elements and oxidative stress indicators as potential biomarkers to determine the CRC risk and progression.
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Affiliation(s)
- Urbashi Basnet
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA; (U.B.); (A.K.)
| | - Abhijeet R. Patil
- Computational Science Program, University of Texas at El Paso, El Paso, TX 79968, USA;
| | - Aditi Kulkarni
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA; (U.B.); (A.K.)
| | - Sourav Roy
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA; (U.B.); (A.K.)
- The Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
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Michel M, Kaps L, Maderer A, Galle PR, Moehler M. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. Cancers (Basel) 2021; 13:2296. [PMID: 34064974 PMCID: PMC8150459 DOI: 10.3390/cancers13102296] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.
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Affiliation(s)
- Maurice Michel
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Leonard Kaps
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, 55131 Mainz, Germany
| | - Annett Maderer
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Peter R. Galle
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Markus Moehler
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
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Liebl MC, Hofmann TG. The Role of p53 Signaling in Colorectal Cancer. Cancers (Basel) 2021; 13:2125. [PMID: 33924934 PMCID: PMC8125348 DOI: 10.3390/cancers13092125] [Citation(s) in RCA: 162] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 12/24/2022] Open
Abstract
The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its polyubiquitination by the E3 ubiquitin ligase MDM2. In response to various stress signals, including DNA damage and aberrant growth signals, the interaction between p53 and MDM2 is blocked and p53 becomes stabilized, allowing p53 to regulate a diverse set of cellular responses mainly through the transactivation of its target genes. The outcome of p53 activation is controlled by its dynamics, its interactions with other proteins, and post-translational modifications. Due to its involvement in several tumor-suppressing pathways, p53 function is frequently impaired in human cancers. In colorectal cancer (CRC), the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning because of alterations in the genes encoding proteins involved in p53 regulation, such as ATM (13%) or DNA-PKcs (11%). TP53 mutations in CRC are usually missense mutations that impair wild-type p53 function (loss-of-function) and that even might provide neo-morphic (gain-of-function) activities such as promoting cancer cell stemness, cell proliferation, invasion, and metastasis, thereby promoting cancer progression. Although the first compounds targeting p53 are in clinical trials, a better understanding of wild-type and mutant p53 functions will likely pave the way for novel CRC therapies.
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Affiliation(s)
- Magdalena C. Liebl
- Institute of Toxicology, University Medical Center Mainz, Johannes Gutenberg University, 55131 Mainz, Germany;
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Baviskar T, Momin M, Liu J, Guo B, Bhatt L. Target Genetic Abnormalities for the Treatment of Colon Cancer and Its Progression to Metastasis. Curr Drug Targets 2021; 22:722-733. [PMID: 33213339 DOI: 10.2174/1389450121666201119141015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/05/2020] [Accepted: 10/12/2020] [Indexed: 12/09/2022]
Abstract
Colorectal carcinogenesis involves various processes from the accumulation of genetic alterations to genetic and epigenetic modulations and chromosomal abnormalities. It also involves mutations in oncogenes and tumour suppressor genes. Genomic instability plays a vital role in CRC. Advances in modern biological techniques and molecular level studies have identified various genes involved in colorectal cancer (CRC). KRAS, BRAF, PI3K, and p53 genes play a significant role in different phases of CRC. Alteration of these genes leads to development or progression and metastasis colon cancer. This review focuses on the role of KRAS, BRAF, PI3KCA, and TP53 genes in carcinogenesis and their significance in various stages of CRC. It also provides insights on specific modulators acting on these genes. Further, this review discusses the mechanism of the pathways involving these genes in carcinogenesis and current molecules and treatment options under various stages of clinical evaluation.
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Affiliation(s)
- Tushar Baviskar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Munira Momin
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Jingwen Liu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, United States
| | - Bin Guo
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, United States
| | - Lokesh Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
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Guo J, Zhu H, Li Q, Dong J, Xiong W, Yu K. SPRY4 suppresses proliferation and induces apoptosis of colorectal cancer cells by repressing oncogene EZH2. Aging (Albany NY) 2021; 13:11665-11677. [PMID: 33879635 PMCID: PMC8109073 DOI: 10.18632/aging.202859] [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: 09/13/2020] [Accepted: 02/16/2021] [Indexed: 11/25/2022]
Abstract
Colorectal cancer (CRC), a common malignant tumor in the digestive tract, is a leading cause of cancer-related death. SPRY4 has been reported to act as a tumor suppressor gene in various tumors. This study aims to assess the role of SPRY4 in colorectal cancer (CRC) and uncover its underlying mechanisms. Firstly, the expression levels of SPRY4 were measured in CRC cell lines. SPRY4-overexpressing or silencing plasmids were transfected into CRC cells to regulate its expression level. CCK-8, colony formation, EdU assay, wound-healing and Transwell assays were performed to determine cell proliferation, invasion and migration abilities. Then, apoptosis was measured by flow cytometry analysis, and the expression of apoptosis-related protein was analyzed by western-blotting. Next, the in vivo tumorigenesis assay was performed in nude mice. According to the results, there was a lower expression of SPRY4 in CRC cell lines compared with normal cell line, and the overexpression of SPRY4 significantly suppressed cell proliferation, migration and invasion, and promoted apoptosis in SW480 cells. Moreover, the enhanced proliferation, invasion and migration upon SPRY4 silencing was reversed by EZH2 inhibition. In addition, we found that the overexpression of SPRY4 inhibited tumorigenesis in vivo by diminishing the size and weight of the tumors. Our study indicates that SPRY4 might be a potential tumor suppressor gene and prognostic factor for patients with CRC.
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Affiliation(s)
- Jia Guo
- Department of Gastroenterology, Sunshine Union Hospital, Weifang 261000, China
| | - Huadong Zhu
- School of Life Science, Nanchang University, Nanchang 330031, China
| | - Qiang Li
- Department of Colorectal Cancer Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Jianhua Dong
- Department of Colorectal Cancer Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Wei Xiong
- Department of Colorectal Cancer Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
| | - Kun Yu
- Department of Colorectal Cancer Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
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de Almeida LC, Calil FA, Machado-Neto JA, Costa-Lotufo LV. DNA damaging agents and DNA repair: From carcinogenesis to cancer therapy. Cancer Genet 2021; 252-253:6-24. [DOI: 10.1016/j.cancergen.2020.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 02/09/2023]
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