Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
Gene. 2024 Nov 15;927:148659. doi: 10.1016/j.gene.2024.148659. Epub 2024 Jun 10.
The inhibition of dipeptidyl- peptidase 4 (DPP-4) is an essential therapy for controlling hyperglycemia in patients with type 2 diabetes (T2DM). However, the role of DPP-4 in cancer is not yet clear, with some studies suggesting that it may either promote or suppress tumors. This makes it crucial to have personalized treatment for diabetic women with cancer to effectively manage their diabetes whilst and preventing cancer mortality. To address this issue, we conducted an integrative in-silico analysis and systematic review of the literature to comprehensively examine the relationship between DPP-4 expression and the effects of its inhibitors on prevalent female malignancies. We specifically chose studies that examined the effects of DPP-4 expression and DPP-4 inhibition (DPP-4i) on prevalent cancers in women, such as breast cancer (BC), ovarian cancer (OV), cervical cancer (CC), and endometrial cancer (EC). These studies comprised those conducted both in vivo and in vitro. The review of the literature indicated that DPP-4i may worsen aggressive traits such as metastasis, Epithelial-to-mesenchymal transition (EMT), and chemotherapy resistance in BC cells. However, cohort studies on diabetic and BC patients did not confirm these findings. In vitro studies indicate that on OV, DPP-4 upregulation has been shown to prevent metastasis, while CCappears to be influenced by DPP-4 expression in terms of cell migration. sitagliptin, a pharmaceutical inhibitor of DPP-4, had a significant impact on reducing adhesion in CC cells in vitro. Overexpression of DPP-4 increased cell migration and proliferation in CC and EC cells, and hence the application of sitagliptin is expected to prevent this effect. On the other hand, the result of in-silico data confirmed that a significant correlation exists between DPP-4 expression and immune cell infiltration in breast, ovarian, cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) as well as downregulated in these cancers compared to their normal tissue samples. Furthermore, a significant (p < 0.05) effect on OS of BC and CESC patients has been reported due to the elevation of DPP-4 methylation on a specific CPG Island. These findings could aid in creating specialized treatments for diabetic women with specific malignancies, but caution should be exercised when considering the patient's medical history and cancer type.
二肽基肽酶 4（DPP-4）的抑制作用是控制 2 型糖尿病（T2DM）患者高血糖的重要治疗方法。然而，DPP-4 在癌症中的作用尚不清楚，一些研究表明它可能促进或抑制肿瘤。这使得为患有癌症的糖尿病女性提供个性化治疗以有效控制其糖尿病并预防癌症死亡率变得至关重要。为了解决这个问题，我们进行了综合的计算机分析和文献系统综述，全面研究了 DPP-4 表达与 DPP-4 抑制剂对常见女性恶性肿瘤的影响之间的关系。我们特别选择了研究 DPP-4 表达及其抑制剂（DPP-4i）对女性常见癌症（如乳腺癌[BC]、卵巢癌[OV]、宫颈癌[CC]和子宫内膜癌[EC]）影响的研究。这些研究包括体内和体外研究。文献综述表明，DPP-4i 可能会使 BC 细胞的转移、上皮间质转化（EMT）和化疗耐药等侵袭性特征恶化。然而，糖尿病和 BC 患者的队列研究并未证实这些发现。体外研究表明，在 OV 中，DPP-4 的上调已被证明可以预防转移，而 CC 似乎受到 DPP-4 表达在细胞迁移方面的影响。西他列汀是 DPP-4 的一种药物抑制剂，它在体外显著降低了 CC 细胞的黏附。DPP-4 的过表达增加了 CC 和 EC 细胞的迁移和增殖，因此预计应用西他列汀可以预防这种作用。另一方面，计算机数据的结果证实，DPP-4 表达与乳腺癌、卵巢癌、宫颈癌鳞状细胞癌和宫颈内膜腺癌（CESC）以及与正常组织样本相比这些癌症中下调的免疫细胞浸润之间存在显著相关性。此外，由于特定 CpG 岛上 DPP-4 甲基化的升高，BC 和 CESC 患者的 OS 报道了显著（p < 0.05）的影响。这些发现可能有助于为患有特定恶性肿瘤的糖尿病女性制定专门的治疗方法，但在考虑患者的病史和癌症类型时应谨慎。
