Friedrich Jana Romy, Meier Clara, Plotz Guido, Zeuzem Stefan, Brieger Angela, Overby Sarah J
Biomedical Research Laboratory, Medical Clinic 1, University Hospital, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany.
Cancers (Basel). 2025 Aug 30;17(17):2857. doi: 10.3390/cancers17172857.
BACKGROUND/OBJECTIVES: Colorectal cancer (CRC) remains a leading cause of cancer-related deaths, with notable sex-specific differences in its incidence, diagnosis, and outcomes. Our previous work identified casein kinase 2 alpha (CK2α) as being capable of impairing DNA mismatch repair (MMR) via phosphorylation of MLH1, thereby increasing the tumor mutational burden. This study aimed to investigate sex-specific differences in CK2α protein expression in CRC.
Immunohistochemical (IHC) analysis was performed on 161 CRC tumors and adjacent normal tissues to quantify the CK2α protein levels. A multi-cohort meta-analysis of proteomic and clinical data was conducted to validate our findings and assess the correlations with age, sex, and relevant signaling pathways.
Female CRC patients exhibited significantly higher CK2α expression than male patients, which was confirmed in two independent cohorts. Additionally, CK2α expression was positively correlated with age in female but not male patients. Cross-cohort correlation analyses linked CK2α levels with key proteins involved in estrogen receptor signaling and aging, including DEAD-box helicase 5 (DDX5), histone deacetylase 1 (HDAC1), proliferating cell nuclear antigen (PCNA), prohibitin-2 (PHB2), H/ACA ribonucleoprotein complex subunit 2 (NHP2), and dual-specificity mitogen-activated protein kinase kinase 3 (MAP2K3).
CK2α is significantly overexpressed in the tumor tissue of female CRC patients and shows a strong age-related correlation. These findings suggest a sex- and age-specific regulatory mechanism potentially influenced by estrogen signaling or menopause. Such dimorphisms underscore the need for sex-specific strategies in CRC biomarker development and therapy.
背景/目的：结直肠癌（CRC）仍然是癌症相关死亡的主要原因，在其发病率、诊断和预后方面存在显著的性别差异。我们之前的研究发现酪蛋白激酶2α（CK2α）能够通过磷酸化MLH1来损害DNA错配修复（MMR），从而增加肿瘤突变负担。本研究旨在调查CRC中CK2α蛋白表达的性别差异。
对161例CRC肿瘤组织及相邻正常组织进行免疫组织化学（IHC）分析，以量化CK2α蛋白水平。对蛋白质组学和临床数据进行多队列荟萃分析，以验证我们的发现，并评估其与年龄、性别和相关信号通路的相关性。
女性CRC患者的CK2α表达明显高于男性患者，这在两个独立队列中得到了证实。此外，CK2α表达在女性患者中与年龄呈正相关，而在男性患者中则不然。跨队列相关性分析将CK2α水平与雌激素受体信号传导和衰老相关的关键蛋白联系起来，包括DEAD盒解旋酶5（DDX5）、组蛋白去乙酰化酶1（HDAC1）、增殖细胞核抗原（PCNA）、抑制素-2（PHB2）、H/ACA核糖核蛋白复合体亚基2（NHP2）和双特异性丝裂原活化蛋白激酶激酶3（MAP2K3）。
CK2α在女性CRC患者的肿瘤组织中显著过表达，且与年龄呈强相关。这些发现表明存在一种可能受雌激素信号或更年期影响的性别和年龄特异性调节机制。这种二态性强调了在CRC生物标志物开发和治疗中采用性别特异性策略的必要性。
