Differential expression of ferroptosis markers, circadian regulators, KLOTHO, and classical tumor suppressors in colorectal cancer according to tumor stage: Influence of age, anatomical location, and correlation patterns.

IF 2 4区 生物学 Q3 CELL BIOLOGY
Miguel A Saez, Cielo Garcia-Montero, Oscar Fraile-Martinez, Ana M Minaya-Bravo, Diego Liviu Boaru, Diego De Leon-Oliva, Patricia De Castro-Martinez, Majd N Michael Alhaddadin, Silvestra Barrena-Blázquez, Laura Lopez-Gonzalez, Luis G Guijarro, Natalio Garcia-Honduvilla, Víctor Roberto Baena Romero, Carlos Daniel Padilla Ansala, Mar Royuela, María Del Val Toledo Lobo, Leonel Pekarek, Roberto Fernández-Baillo Gallego de la Sacristana, Mauricio Hernández-Fernández, Montserrat Chao Crecente, Melchor Alvarez-Mon, Raul Diaz-Pedrero, Miguel A Ortega
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引用次数: 0

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with an incidence projected to rise significantly worldwide. While TNM staging remains the cornerstone of prognosis and treatment decisions, additional biomarkers are needed to enhance predictive accuracy and therapeutic targeting. Ferroptosis, an iron-dependent cell death pathway, has emerged as a key regulator of CRC progression and therapy resistance. Circadian rhythms, KLOTHO, and tumor suppressors, such as p53, CDKN1A (p21), and Rb, also play crucial roles in CRC biology. Integrating TNM staging with molecular markers and patient-specific variables offers a more precise, personalized approach to CRC management. In the present work, we analyze the histopathological expression of KLOTHO, ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian regulators (CLOCK, BMAL1, PER1, and PER2), and classical tumor suppressors (p53, p21, and Rb) in a cohort of 63 patients diagnosed with CRC. Besides, we have considered important clinical variables, like sex, age, and anatomical location, in our statistical analysis; correlation with the protein expression of these markers was also included for each stage (T1, T2, and T3). Our study reveals that advanced CRC stages (primarily T3) exhibit increased expression of ferroptosis markers (TFRC, ALOX5, ACSL4, and GPX4) and tumor suppressors (p53, p21, and Rb), alongside reduced histopathological detection of KLOTHO and circadian markers (BMAL1, CLOCK, PER1, and PER2) compared with earlier stages. Age, but not sex, influenced the expression of several markers. Tumor location also played a role, with right-sided CRCs showing significant stage-related differences in ferroptosis, tumor suppressor, and BMAL1, whereas left-sided tumors exhibited variations primarily in circadian markers (CLOCK, PER1, and PER2). Correlation analyses across tumor stages indicate dynamic shifts, with tumor suppressors maintaining positive associations with ferroptosis markers and anti-aging/circadian markers showing stage-dependent changes. Despite the inherent limitations of our study, these findings highlight the evolving biomarker landscape in CRC progression, although further research is needed to elucidate their clinical implications.

根据肿瘤分期,结直肠癌中铁下垂标志物、昼夜节律调节因子、KLOTHO和经典肿瘤抑制因子的差异表达:年龄、解剖位置和相关模式的影响
结直肠癌(CRC)是癌症相关死亡的主要原因,预计全球发病率将显著上升。虽然TNM分期仍然是预后和治疗决策的基础,但需要其他生物标志物来提高预测准确性和治疗靶向性。铁凋亡是一种铁依赖性细胞死亡途径,已成为结直肠癌进展和治疗耐药的关键调节因子。昼夜节律、KLOTHO和肿瘤抑制因子,如p53、CDKN1A (p21)和Rb,在结直肠癌生物学中也起着至关重要的作用。将TNM分期与分子标记和患者特异性变量相结合,为CRC管理提供了更精确、更个性化的方法。在本研究中,我们分析了63例结直肠癌患者中KLOTHO、铁吊标志物(TFRC、ALOX-5、acls -4和GPX-4)、昼夜节律调节因子(CLOCK、BMAL1、PER1和PER2)和经典肿瘤抑制因子(p53、p21和Rb)的组织病理学表达。此外,我们在统计分析中考虑了重要的临床变量,如性别、年龄和解剖位置;每个阶段(T1、T2和T3)与这些标记物蛋白表达的相关性也被包括在内。我们的研究表明,与早期相比,晚期CRC(主要是T3)表现出高铁凋亡标志物(TFRC、ALOX5、ACSL4和GPX4)和肿瘤抑制因子(p53、p21和Rb)的表达增加,同时KLOTHO和昼夜节律标志物(BMAL1、CLOCK、PER1和PER2)的组织病理学检测减少。年龄,而不是性别,影响了几种标记的表达。肿瘤位置也起了一定的作用,右侧肿瘤在铁下垂、肿瘤抑制因子和BMAL1上表现出显著的分期相关差异,而左侧肿瘤主要在昼夜节律标志物(CLOCK、PER1和PER2)上表现出差异。不同肿瘤分期的相关分析显示出动态变化,肿瘤抑制因子与铁下垂标志物保持正相关,抗衰老/昼夜节律标志物显示出分期依赖性变化。尽管我们的研究存在固有的局限性,但这些发现强调了CRC进展中不断变化的生物标志物景观,尽管需要进一步的研究来阐明其临床意义。
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来源期刊
Histology and histopathology
Histology and histopathology 生物-病理学
CiteScore
3.90
自引率
0.00%
发文量
232
审稿时长
2 months
期刊介绍: HISTOLOGY AND HISTOPATHOLOGY is a peer-reviewed international journal, the purpose of which is to publish original and review articles in all fields of the microscopical morphology, cell biology and tissue engineering; high quality is the overall consideration. Its format is the standard international size of 21 x 27.7 cm. One volume is published every year (more than 1,300 pages, approximately 90 original works and 40 reviews). Each volume consists of 12 numbers published monthly online. The printed version of the journal includes 4 books every year; each of them compiles 3 numbers previously published online.
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