Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
Int J Mol Sci. 2023 Jan 23;24(3):2275. doi: 10.3390/ijms24032275.
Colorectal cancer is a notorious disease, with almost half of the patients succumbing to the disease. The prevalence and incidence rates of colorectal cancer are increasing in many parts of the world, highlighting the need to discover new biomarkers for diagnosis and therapy. Caldesmon (CaD), an actin-binding protein that plays a significant role in controlling cell motility, has emerged as a promising biomarker. The gene encodes CaD as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight (h-CaD), expressed in smooth muscle, and low-molecular-weight (l-CaD), expressed in nonsmooth muscle cells. Most studies have suggested an oncogenic role of CaD in colorectal cancer, but the exact subcellular localization of the two CaD isoforms in tumor cells and stroma have not been clarified yet. Here, we analyzed tissue samples from 262 colorectal cancer patients by immunohistochemistry analysis using specific antibodies for l-CaD and h-CaD. The results showed elevated cytoplasmic expression levels of l-Cad in 187/262 (71.4%) cases. l-Cad was expressed at low levels in the normal colon mucosa and was also consistently expressed in the cancer-associated stroma of all cases, suggesting that it could play a role in modulating the tumor microenvironment. l-CaD expression in cancer cells was associated with preinvasive stages of cancer. Survival analysis indicated that patients with high l-CaD expression in tumor cells could respond poorly to selective chemotherapeutic 5FU, but not combination chemotherapy. h-CaD was expressed in colonic and vascular smooth muscle cells as expected and to a lesser extent in the tumor-associated stroma, but it was not expressed in the cancer cells or normal colon mucosal epithelial cells. Collectively, these data clarify how the expression patterns of CaD isoforms in colorectal cancer can have applications in the management of colorectal cancer patients.
结直肠癌是一种恶性疾病，近半数患者死于该病。在世界许多地区，结直肠癌的患病率和发病率正在上升，这凸显了寻找新的诊断和治疗生物标志物的必要性。钙调蛋白（CaD）是一种肌动蛋白结合蛋白，在控制细胞运动方面发挥着重要作用，已成为一种很有前途的生物标志物。该基因编码的 CaD 有多个转录本，主要编码两种蛋白异构体：高分子量（h-CaD），在平滑肌中表达，和低分子量（l-CaD），在非平滑肌细胞中表达。大多数研究表明 CaD 在结直肠癌中具有致癌作用，但两种 CaD 异构体在肿瘤细胞和基质中的确切亚细胞定位尚未阐明。在这里，我们使用针对 l-CaD 和 h-CaD 的特异性抗体，通过免疫组织化学分析，对 262 例结直肠癌患者的组织样本进行了分析。结果显示，187/262（71.4%）例的细胞质 l-Cad 表达水平升高。l-Cad 在正常结肠黏膜中的表达水平较低，在所有病例的癌相关基质中也一致表达，表明它可能在调节肿瘤微环境中发挥作用。癌细胞中的 l-CaD 表达与癌症的浸润前阶段有关。生存分析表明，肿瘤细胞中 l-CaD 高表达的患者对选择性化疗药物 5FU 反应不佳，但对联合化疗反应良好。h-CaD 如预期的那样在结肠和血管平滑肌细胞中表达，在肿瘤相关基质中的表达程度较低，但在癌细胞或正常结肠黏膜上皮细胞中不表达。总的来说，这些数据阐明了结直肠癌中 CaD 异构体的表达模式如何应用于结直肠癌患者的管理。
