Comprehensive Analysis of Estrogen Receptor 1 Dysregulation in Liver Hepatocellular Carcinoma: Implications for Prognosis and Therapeutic Targeting
Download PDF

Keywords

Estrogen receptor 1
Liver hepatocellular carcinoma
Biomarker
Prognosis

DOI

10.26689/par.v8i3.6865

Submitted : 2024-05-28
Accepted : 2024-06-12
Published : 2024-06-27

Abstract

The study investigates the expression pattern and regulatory mechanisms of estrogen receptor 1 (ESR1) in liver hepatocellular carcinoma (LIHC) through comprehensive bioinformatics analysis. Utilizing UALCAN and GEPIA2 databases, significant down-regulation of ESR1 expression is observed in LIHC samples compared to normal controls, indicating its potential role in tumor progression. Further analysis reveals consistent down-regulation across different clinical variables including patient age, gender, race, and various stages of LIHC, affirming the regulatory role of ESR1 in tumor development and progression. Additionally, promoter methylation analysis demonstrates hypermethylation of ESR1 in LIHC samples, negatively correlating with its expression. This association persists across different clinical parameters, emphasizing the inverse relationship between ESR1 methylation and expression levels. Survival analysis indicates that up-regulation of ESR1 is associated with better overall survival, suggesting its potential as a prognostic biomarker in LIHC. Furthermore, genetic mutation analysis using cBioPortal reveals a spectrum of alterations in ESR1, including amplification, missense mutation, deep deletion, splice mutation, and truncating mutation, highlighting the genetic complexity of ESR1 in LIHC. These findings collectively contribute to a deeper understanding of ESR1 dysregulation in LIHC and its clinical implications as a potential therapeutic target and prognostic marker.

References

Krieghoff-Henning E, Folkerts J, Penzkofer AS, et al., 2017, Cancer – An Overview. Med Monatsschr Pharm, 40(2): 48–54.

Bray F, Laversanne M, Sung H, et al., 2024, Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 74(3): 229–263.

Upadhyay A, 2021, Cancer: An Unknown Territory; Rethinking Before Going Ahead. Genes Dis, 8(5): 655–661.

Kaur H, Bhalla S, Raghava GPS, 2019, Classification of Early and Late Stage Liver Hepatocellular Carcinoma Patients from Their Genomics and Epigenomics Profiles. PLoS One, 14(9): e0221476.

Gao S, Gang J, Yu M, et al., 2021, Computational Analysis for Identification of Early Diagnostic Biomarkers and Prognostic Biomarkers of Liver Cancer Based on GEO and TCGA Databases and Studies on Pathways and Biological Functions Affecting the Survival Time of Liver Cancer. BMC Cancer, 2021(21): 1–15.

Sung H, Ferlay J, Siegel RL, et al., 2021, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71(3): 209–249.

Balogh J, Victor III D, Asham EH, et al., 2016, Hepatocellular Carcinoma: A Review. Journal of Hepatocellular Carcinoma, (2016): 41–53.

Zhou H, Song T, 2021, Conversion Therapy and Maintenance Therapy for Primary Hepatocellular Carcinoma. BioScience Trends, 15(3): 155–160.

Long J, Lin J, Wang A, et al., 2017, PD-1/PD-L Blockade in Gastrointestinal Cancers: Lessons Learned and the Road Toward Precision Immunotherapy. Journal of Hematology & Oncology, (10): 1–21.

Poon D, Anderson BO, Chen LT, et al., 2009, Management of Hepatocellular Carcinoma in Asia: Consensus Statement from the Asian Oncology Summit 2009. The Lancet Oncology, 10(11): 1111–1118.

Huang A, Yang XR, Chung WY, et al., 2020, Targeted Therapy for Hepatocellular Carcinoma. Signal Transduction and Targeted Therapy, 5(1): 146.

Hofmann WK, 2006, Gene Expression Profiling by Microarrays: Clinical Implications, Cambridge University Press, Cambridge.

Higa GM, Fell RG, 2013, Sex Hormone Receptor Repertoire in Breast Cancer. International Journal of Breast Cancer, (2013): 284036.

Huang B, Warner M, Gustafsson JÅ, 2015, Estrogen Receptors in Breast Carcinogenesis and Endocrine Therapy. Molecular and Cellular Endocrinology, (418): 240–244.

De Santo I, McCartney A, Migliaccio I, et al., 2019, The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy. Cancers (Basel), 11(12): 1894.

Bhat M, Pasini E, Pastrello C, et al., 2021, Estrogen Receptor 1 Inhibition of Wnt/?-Catenin Signaling Contributes to Sex Differences in Hepatocarcinogenesis. Front Oncol, (11): 777834.

Liang J, Lv J, Liu Z, 2015, Identification of Dysfunctional Biological Pathways and Their Synergistic Mechanism in Hepatocellular Carcinoma Process. Experimental and Molecular Pathology, 98(3): 540–545.

Hishida M, Nomoto S, Inokawa Y, et al., 2013, Estrogen Receptor 1 Gene as a Tumor Suppressor Gene in Hepatocellular Carcinoma Detected by Triple-Combination Array Analysis. International journal of oncology, 43(1): 88–94.

Zundelevich A, Dadiani M, Kahana-Edwin S, et al., 2020, ESR1 Mutations are Frequent in Newly Diagnosed Metastatic and Loco-Regional Recurrence of Endocrine-Treated Breast Cancer and Carry Worse Prognosis. Breast Cancer Research, 22(1): 16.

Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, et al., 2013, D538G Mutation in Estrogen Receptor-?: A Novel Mechanism for Acquired Endocrine Resistance in Breast Cancer. Cancer Research, 73(23): 6856–6864.

Jeselsohn R, Yelensky R, Buchwalter G, et al., 2014, Emergence of Constitutively Active Estrogen Receptor-? Mutations in Pretreated Advanced Estrogen Receptor–Positive Breast Cancer. Clinical Cancer Research, 20(7): 1757–1767.

Toy W, Shen Y, Won H, et al., 2013, ESR1 Ligand-Binding Domain Mutations in Hormone-Resistant Breast Cancer. Nature Genetics, 45(12): 1439–1445.

Gelsomino L, Gu G, Rechoum Y, et al., 2016, ESR1 Mutations Affect Anti-Proliferative Responses to Tamoxifen Through Enhanced Cross-Talk with IGF Signaling. Breast Cancer Research and Treatment, (157): 253–265.

Toy W, Weir H, Razavi P, et al., 2017, Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists. Cancer Discovery, 7(3): 277–287.

Chandrashekar DS, Bashel B, Balasubramanya SAH, et al., 2017, UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia, 19(8): 649–658.

Tang Z, Li C, Kang B, et al., 2017, GEPIA: A Web Server for Cancer and Normal Gene Expression Profiling and Interactive Analyses. Nucleic Acids Research, 45(W1): W98–W102.

Gy?rffy B, Surowiak P, Budczies J, et al., 2013, Online Survival Analysis Software to Assess the Prognostic Value of Biomarkers Using Transcriptomic Data in Non-Small-Cell Lung Cancer. PLoS One, 8(12): e82241.

Cerami E, Gao J, Dogrusoz U, et al., 2012, The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery, 2(5): 401–404.

Luczak MW, Jagodzi?ski PP, 2006, The Role of DNA Methylation in Cancer Development. Folia Histochem Cytobiol, 44(3): 143–154.

Estes C, Razavi H, Loomba R, et al., 2018, Modeling the Epidemic of Nonalcoholic Fatty Liver Disease Demonstrates an Exponential Increase in Burden of Disease. Hepatology, 67(1): 123–133.

Usman M, Hameed Y, 2022, GNB1, a Novel Diagnostic and Prognostic Potential Biomarker of Head and Neck and Liver Hepatocellular Carcinoma. Journal of Cancer Research and Therapeutics, 20(2).

Chandrashekar DS, Bashel B, Balasubramanya SAH, et al., 2017, UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia, 19(8): 649–658.

McCleary-Wheeler AL, Lomberk GA, Weiss FU, et al., 2013, Insights into the Epigenetic Mechanisms Controlling Pancreatic Carcinogenesis. Cancer Lett, 328(2): 212–221.

Usman M, Hameed Y, Ahmad M, et al., 2022, Breast Cancer Risk and Human Papillomavirus Infection: A Bradford Hill Criteria Based Evaluation. Infect Disord Drug Targets, 22(4): e200122200389.

Hameed Y, Usman M, Liang S, et al., 2021, Novel Diagnostic and Prognostic Biomarkers of Colorectal Cancer: Capable to Overcome the Heterogeneity-Specific Barrier and Valid for Global Applications. PLoS One, 16(9): e0256020.

Zhang L, Sahar AM, Li C, et al., 2022, A Detailed Multi-Omics Analysis of GNB2 Gene in Human Cancers. Braz J Biol, (84): e260169.

Välk K, Vooder T, Kolde R, et al., 2010, Gene Expression Profiles of Non-Small Cell Lung Cancer: Survival Prediction and New Biomarkers. Oncology, 79(3–4): 283–292.

Jenssen TK, Kuo WP, Stokke T, et al., 2002, Associations Between Gene Expressions in Breast Cancer and Patient Survival. Hum Genet, 111(4–5): 411–420.