E Ying, Xue Hang, Zhang Cong-Yu, Zhao Ming-Zhen, Zheng Hua-Chuan
Department of Oncology and Center Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, PR China.
Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, PR China.
Histol Histopathol. 2023 Apr;38(4):453-465. doi: 10.14670/HH-18-534. Epub 2022 Oct 18.
Parafibromin is a protein encoded by the oncosuppressor CDC73 gene, whose mutation results in hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid carcinoma. Down-regulation of parafibromin is linked to lung, gastric, colorectal, and ovarian cancer tumorigenesis. Parafibromin expression was detected by RT-PCR, bioinformatics analysis, Western blot, and immunohistochemistry; and compared with clinicopathological characteristics of breast cancer. CDC73-related genes and pathways were analyzed using bioinformatics analysis. Parafibromin expression was increased in breast cancer compared to normal tissues at both mRNA and protein levels (p<0.05). Among triple-negative breast cancers, it was higher in basal-like 1 than basal-like 2 patients (p<0.05) and mesenchymal than immunomodulatory patients (p<0.05). CDC73 mRNA expression was positively correlated with white race, non-infiltrating immune cells, favorable luminal subtypes of PAM50, and prognosis of breast cancer patients (p<0.05). The differential genes of CDC73 were classified into enzyme inhibitors, peptidase, and keratinization by KEGG (p<0.05). Similarly, it was classified into ribosomes, TGF-β, oxidation phosphorylation, inositol phosphate metabolism, arachidonic acid metabolism, linoleic acid metabolism, ERBB, and VEGF signaling pathways by GSEA (p<0.05). The positively-correlated genes of CDC73 were involved in cell mobility, response to interferon α, nuclear pore and basket, and histone methyltransferase. The negatively-correlated genes of CDC73 were involved in the mitochondrial respiratory chain, thermogenesis, and ribosomes. Parafibromin expression was higher in invasive ductal than lobular carcinoma (p<0.05) and mucinous adenocarcinoma than others (p<0.05). Parafibromin immunoreactivity as an independent factor was positively associated with an increased overall survival rate of breast cancer patients (p<0.05). These findings suggest that up-regulation of parafibromin in breast cancer patients is closely linked to a favorable prognosis. It is involved in tumorigenesis and subsequent progression by regulating metabolism, ribosomes, and cytokines.
副纤维蛋白是一种由抑癌基因CDC73编码的蛋白质，其突变会导致甲状旁腺功能亢进-颌骨肿瘤综合征（HPT-JT）和甲状旁腺癌。副纤维蛋白的下调与肺癌、胃癌、结直肠癌和卵巢癌的肿瘤发生有关。通过逆转录聚合酶链反应（RT-PCR）、生物信息学分析、蛋白质免疫印迹法和免疫组织化学检测副纤维蛋白的表达；并与乳腺癌的临床病理特征进行比较。使用生物信息学分析方法分析与CDC73相关的基因和信号通路。与正常组织相比，乳腺癌中副纤维蛋白在mRNA和蛋白质水平上均升高（p<0.05）。在三阴性乳腺癌中，基底样1型患者的副纤维蛋白表达高于基底样2型患者（p<0.05），间充质型患者的副纤维蛋白表达高于免疫调节型患者（p<0.05）。CDC73 mRNA表达与白种人、非浸润性免疫细胞、PAM50的有利管腔亚型以及乳腺癌患者的预后呈正相关（p<0.05）。通过京都基因与基因组百科全书（KEGG）分析，CDC73的差异基因被分类为酶抑制剂、肽酶和角质化相关基因（p<0.05）。同样，通过基因集富集分析（GSEA），它被分类为核糖体、转化生长因子-β（TGF-β）、氧化磷酸化、肌醇磷酸代谢、花生四烯酸代谢、亚油酸代谢、表皮生长因子受体（ERBB）和血管内皮生长因子（VEGF）信号通路（p<0.05）。与CDC73呈正相关的基因参与细胞迁移、对α干扰素的反应、核孔和核篮以及组蛋白甲基转移酶。与CDC73呈负相关的基因参与线粒体呼吸链、产热和核糖体相关过程。浸润性导管癌中的副纤维蛋白表达高于小叶癌（p<0.05），黏液腺癌中的副纤维蛋白表达高于其他类型（p<0.05）。副纤维蛋白免疫反应性作为一个独立因素与乳腺癌患者总体生存率的提高呈正相关（p<0.05）。这些发现表明，乳腺癌患者中副纤维蛋白的上调与良好的预后密切相关。它通过调节代谢、核糖体和细胞因子参与肿瘤发生及后续进展。
