Background: Treatment of metastatic cancer remains a challenge, because cancer cells acquire resistance even to the most contemporary therapies. This study analyzed the role of the phosphoprotein Stathmin 1 (STMN1) in regulating cancer cell growth and metastatic potential.Methods: Public datasets with metastatic castration-resistant prostate cancer (mCRPC) and breast cancer (BC) were analyzed to determine the interrelationship between STMN1, hepatocyte growth factor (HGF) and MET proto-oncogene (MET) expression, overall survival, and response to chemotherapy. Site-directed mutagenesis, cell cycle analysis, proliferation, and migration and invasion assays determined the impact of STMN1 phosphorylation on proliferation and metastatic potential.Results: Increased STMN1 associates with HGF and MET gene expression in mCRPC, and taxane chemotherapy further increases HGF expression. STMN1 and HGF are highest, and overall survival is poorest in mCRPC in the liver compared to other sites, implying the metastatic site influences their expression levels and potentially the pattern of metastatic spread. Increased STMN1 and MET also predict taxane responsiveness in BC patients. Analysis of STMN1 serine (S)16, 25, 38, and 63 determined that total (t) STMN1 and STMN1 S16 phosphorylation (pSTMN1S16) are co-regulated by HGF/MET during cell cycle progression, pSTMN1S16alone can promote cell proliferation, and pSTMN1S16shortens the cell cycle similar to HGF treatment, while STMN1S16dephosphorylation lengthens the cell cycle to arrest cell growth in G2/M, similar to HGF plus the MET inhibitor AMG337. Importantly, STMN1S16does not promote metastasis.Conclusions: Selectively inhibiting STMN1S16phosphorylation may provide an alternative strategy for inhibiting MET-mediated cell growth to eliminate metastatic cancer cells and inhibit further metastasis.
背景：转移性癌症的治疗仍面临挑战，因为癌细胞甚至对最先进的疗法也会产生耐药性。本研究分析了磷蛋白Stathmin 1（STMN1）在调控癌细胞生长和转移潜能中的作用。 方法：通过分析转移性去势抵抗性前列腺癌（mCRPC）和乳腺癌（BC）的公共数据集，确定STMN1、肝细胞生长因子（HGF）和MET原癌基因（MET）表达之间的相互关系，以及它们与总生存期和化疗反应之间的关联。采用定点突变、细胞周期分析、增殖实验以及迁移和侵袭实验，评估STMN1磷酸化对细胞增殖和转移潜能的影响。 结果：在mCRPC中，STMN1升高与HGF和MET基因表达相关，紫杉烷类化疗进一步增加HGF表达。与其他转移部位相比，肝脏mCRPC中STMN1和HGF水平最高，总生存期最差，表明转移部位影响其表达水平，并可能影响转移扩散模式。STMN1和MET升高还可预测BC患者对紫杉烷类药物的反应性。对STMN1丝氨酸（S）16、25、38和63位点的分析表明，总STMN1（tSTMN1）和STMN1 S16磷酸化（pSTMN1S16）在细胞周期进程中受HGF/MET共同调控；pSTMN1S16单独即可促进细胞增殖，且与HGF处理类似，pSTMN1S16可缩短细胞周期；而STMN1 S16去磷酸化则延长细胞周期，使细胞生长停滞于G2/M期，这与HGF联合MET抑制剂AMG337的作用相似。重要的是，STMN1 S16不促进转移。 结论：选择性抑制STMN1 S16磷酸化可能为抑制MET介导的细胞生长提供一种替代策略，从而消除转移性癌细胞并抑制进一步转移。
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