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. Methods: 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. Results: 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). Conclusions: 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）仍是癌症相关死亡的主要原因之一，其发病率、诊断和预后存在显著的性别差异。我们先前的研究发现，酪蛋白激酶2α（CK2α）可通过磷酸化MLH1损害DNA错配修复（MMR），从而增加肿瘤突变负荷。本研究旨在探讨CK2α蛋白在CRC中表达的性别特异性差异。 **方法：** 对161例CRC肿瘤组织及癌旁正常组织进行免疫组织化学（IHC）分析，以量化CK2α蛋白水平。同时，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、性别及相关信号通路的相关性。 **结果：** 女性CRC患者的CK2α表达显著高于男性患者，该结果在两个独立队列中得到证实。此外，在女性患者中，CK2α表达与年龄呈正相关，而在男性患者中未观察到这种相关性。跨队列相关性分析显示，CK2α水平与雌激素受体信号通路和衰老相关的关键蛋白存在关联，包括DEAD-box解旋酶5（DDX5）、组蛋白去乙酰化酶1（HDAC1）、增殖细胞核抗原（PCNA）、抗增殖蛋白2（PHB2）、H/ACA核糖核蛋白复合物亚基2（NHP2）以及双特异性丝裂原活化蛋白激酶激酶3（MAP2K3）。 **结论：** CK2α在女性CRC患者的肿瘤组织中显著过表达，并显示出强烈的年龄相关性。这些发现提示存在一种可能受雌激素信号或绝经影响的、具有性别和年龄特异性的调控机制。此类性别二态性强调了在CRC生物标志物开发和治疗中采取性别特异性策略的必要性。
CK2α Overexpression in Colorectal Cancer: Evidence for Sex- and Age-Linked Differences
肿瘤(癌症)患者之家