SHP-1在膀胱癌症细胞EMT调节中的肿瘤抑制作用的证据

摘要(中文译文)

含Src同源2结构域的蛋白酪氨酸磷酸酶1（SHP-1），也称为非受体型蛋白酪氨酸磷酸酶6，在乳腺癌、肝细胞癌和前列腺癌中发挥抑癌基因的作用，而在胶质母细胞瘤和宫颈癌中则作为癌基因发挥作用。此前对癌症基因组图谱（TCGA）数据集的分析显示，膀胱肿瘤中SHP-1转录水平较低与较差的总生存期相关。本研究旨在评估SHP-1在膀胱癌中的作用，并评估其在膀胱癌细胞系中强制表达和敲低的功能影响。在19个膀胱癌细胞系和26份膀胱组织中评估了SHP-1的表达。采用慢病毒转导在四个细胞系中敲低或过表达SHP-1，随后通过Western blot分析SHP-1及pAkt/Akt蛋白表达。SHP-1蛋白水平在高侵袭性细胞系（< 0.001）和肌层浸润性肿瘤（< 0.05）中显著降低。功能研究表明，SHP-1的调控影响了上皮-间质转化（EMT）表型。SHP-1表达与E-钙黏蛋白表达呈正相关（< 0.001），与N-钙黏蛋白（< 0.01）和波形蛋白（< 0.05）表达呈负相关。膀胱癌细胞系中SHP-1表达的改变影响了增殖、侵袭和迁移（< 0.05）。对转导细胞系的RNA-seq分析显示，与EMT相关的基因集以及涉及MYC、PI3K、Akt和mTOR的信号通路出现富集。此外，SHP-1的改变影响了pAkt/Akt比值（< 0.05）。总体而言，SHP-1蛋白表达较低与膀胱癌细胞系和膀胱肿瘤中更具侵袭性的表型相关。在我们有限的数据集中，SHP-1表达降低与肌层浸润性疾病相关，提示其可能与更晚期的肿瘤生物学相关，这与TCGA将SHP-1转录表达降低与较差生存率相关联的结果一致。我们的数据提供了初步的功能证据，表明SHP-1可能调控膀胱癌中的Akt信号通路。总之，这些结果支持进一步研究SHP-1作为膀胱癌可能的抑癌基因、候选预后生物标志物和潜在治疗靶点。

Abstract

Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), also known as protein tyrosine phosphatase non-receptor type 6, functions as a tumor suppressor in breast, hepatocellular, and prostate cancers and an oncogene in glioblastoma and cervical cancer. A previous analysis of The Cancer Genome Atlas (TCGA) dataset revealed that lower SHP-1 transcript levels in bladder tumors were associated with poorer overall survival. This study aimed to evaluate the role of SHP-1 in bladder cancer and to assess the functional impact of its forced expression and knockdown in bladder carcinoma cell lines. SHP-1 expression was assessed in 19 bladder cancer cell lines and 26 bladder tissues. Lentiviral transduction was used to knock down or overexpress SHP-1 in four cell lines, followed by Western blot analysis of SHP-1 and pAkt/Akt protein expression. SHP-1 protein levels were significantly lower in highly invasive cell lines ( < 0.001) and muscle-invasive tumors ( < 0.05). Functional studies demonstrated that SHP-1 modulation influenced the epithelial-mesenchymal transition (EMT) phenotype. SHP-1 expression was positively correlated with E-cadherin expression ( < 0.001) and negatively correlated with N-cadherin ( < 0.01) and Vimentin ( < 0.05) expression. Alteration of SHP-1 expression in bladder cancer cell lines affected proliferation, invasion, and migration ( < 0.05). RNA-seq analysis of the transduced cell lines revealed enrichment of gene sets related to EMT and signaling pathways involving MYC, PI3K, Akt, and mTOR. Furthermore, SHP-1 alteration impacted pAkt/Akt ratios ( < 0.05). Collectively, lower SHP-1 protein expression correlated with more aggressive phenotypes in bladder cancer cell lines and bladder tumors. In our limited dataset, reduced SHP-1 expression correlated with muscle-invasive disease, suggesting a potential link to more advanced tumor biology, consistent with TCGA associating reduced SHP-1 transcript expression to poorer survival rates. Our data provide preliminary functional evidence that SHP-1 may modulate Akt signaling in bladder cancer. Together, these results support further investigation of SHP-1 as a possible tumor suppressor, candidate prognostic biomarker, and potential therapeutic target in bladder cancer.

如何引用

Cancers 的其他文献

• MDM4处于十字路口：超越p53和MDM2
• 急性髓系白血病患者口服地西他滨/西达珠尿苷治疗期间分子畸变的连续测定
• 崩解蛋白和金属蛋白酶（ADAM）蛋白作为结直肠癌癌症临床相关生物标志物的潜力：综合分析
• 肺癌前的结核病：揭示20年后证据中关键差距的现代Meta-Analysis
• 癌症脑转移三阴性：流行病学、分子病理生物学和治疗前沿的综合综述
• 早期癌症宫颈癌一期根治术后的预后生存模型
• 在猪皮肤模型中使用标准护理分级方案对电子闪光放射治疗的可行性和皮肤毒性进行初步评估
• 可切除非小细胞肺癌新辅助治疗后术后辅助治疗的反应适应效益：一项单中心回顾性队列研究
• 使用Japonica阵列NEO，在乳腺癌症中，单核苷酸多态性与曲妥珠单抗Deruxtecan-诱导的间质性肺病之间的关联
• 埃塞俄比亚除吸烟外的肺癌危险因素：一项多中心匹配病例对照研究