SHCBP1 促进肿瘤细胞增殖、迁移和侵袭，并与前列腺癌不良预后相关。
SHCBP1 promotes tumor cell proliferation, migration, and invasion, and is associated with poor prostate cancer prognosis.
机构信息
Departments of Urology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Rd, Yuzhong District, Chongqing, 400016, China.
Departments of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
出版信息
J Cancer Res Clin Oncol. 2020 Aug;146(8):1953-1969. doi: 10.1007/s00432-020-03247-1. Epub 2020 May 23.
OBJECTIVE
Prostate cancer (PCa) is an aggressive tumor. SHC SH2-domain-binding protein 1 (SHCBP1) has been identified frequently upregulated in various cancers, in addition to PCa. The aims of this study were to determine the relationships between SHCBP1 and clinicopathological characteristics of PCa and to explore the role of SHCBP1 in PCa proliferation and progression.
METHODS
Tissue microarray and immunohistochemistry were used to determine the prognostic significance of SHCBP1. The relationship between clinicopathological characteristics of PCa and SHCBP1 was then analyzed using Cox regression analyses. To investigate SHCBP1 functions in vitro and in vivo, we knocked down SHCBP1 in PCa cell lines and established xenograft mice models. A series of cytological function assays were utilized to determine the role of SHCBP1 in cell proliferation, migration, invasion, and apoptosis.
RESULTS
SHCBP1 was significantly upregulated in PCa tissues compared with BPH tissues. Patients with a higher expression of SHCBP1 were associated with poor survival outcomes than those with a lower expression of SHCBP1. Lentivirus-mediated shRNA knockdown of SHCBP1 in prostate cancer cell lines diminished cell growth, migration, and invasion dramatically both in vitro and in vivo, accompanied by an enhanced expression of large tumor suppressor 1 (LATS1) and tumor protein P53 (TP53) and inhibition of MDM2 proto-oncogene (MDM2), which suggested that SHCBP1 may promote proliferation and invasion in vitro via the LATS1-MDM2-TP53 pathway. The results of cycloheximide (CHX) and MG-132 assays indicated that SHCBP1 knockdown could attenuate the degradation of TP53 by the proteasome, prolong the half-life of TP53, and enhance the stabilization of TP53.
CONCLUSION
These findings suggest that SHCBP1 overexpression contributes to PCa progression and that targeting SHCBP1 might be therapeutically beneficial to patients with PCa.
目的
前列腺癌（PCa）是一种侵袭性肿瘤。除了 PCa 之外，SHC SH2 结构域结合蛋白 1（SHCBP1）已被确定在各种癌症中经常上调。本研究的目的是确定 SHCBP1 与 PCa 的临床病理特征之间的关系，并探讨 SHCBP1 在 PCa 增殖和进展中的作用。
方法
使用组织微阵列和免疫组织化学来确定 SHCBP1 的预后意义。然后使用 Cox 回归分析分析 PCa 的临床病理特征与 SHCBP1 之间的关系。为了研究 SHCBP1 在体外和体内的功能，我们在 PCa 细胞系中敲低 SHCBP1 并建立异种移植小鼠模型。利用一系列细胞学功能测定来确定 SHCBP1 在细胞增殖、迁移、侵袭和凋亡中的作用。
结果
与 BPH 组织相比，SHCBP1 在 PCa 组织中明显上调。与 SHCBP1 低表达的患者相比，SHCBP1 高表达的患者生存结局较差。慢病毒介导的 shRNA 敲低前列腺癌细胞系中的 SHCBP1 ，在体外和体内均显著抑制细胞生长、迁移和侵袭，同时增强大肿瘤抑制因子 1（LATS1）和肿瘤蛋白 P53（TP53）的表达，并抑制原癌基因 MDM2（MDM2），这表明 SHCBP1 可能通过 LATS1-MDM2-TP53 通路促进体外增殖和侵袭。细胞周期蛋白 D1（CHX）和 MG-132 测定的结果表明，SHCBP1 敲低可减弱蛋白酶体对 TP53 的降解，延长 TP53 的半衰期，并增强 TP53 的稳定性。
结论
这些发现表明 SHCBP1 的过表达有助于 PCa 的进展，靶向 SHCBP1 可能对 PCa 患者具有治疗益处。
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