Stathmin 1: a novel therapeutic target for anticancer activity

Stathmin 1 (STMN1), also known as p17, p18, p19, 19K, metablastin, oncoprotein 18, LAP 18 and Op18, is a 19 kDa cytosolic protein. It was the first discovered member of a family of phylogenetically related microtubule-destabilizing phosphoproteins critically involved in the construction and function of the mitotic spindle. A threshold level of STMN1 is required for orderly progression through mitosis in a variety of cell types. STMN1 is overexpressed across a broad range of human malignancies (leukemia, lymphoma, neuroblastoma; ovarian, prostatic, breast and lung cancers and mesothelioma). It is also upregulated in normally proliferating cell lines but is only rarely upregulated in nonproliferating cell lines with the exception of neurons, anterior pituitary cells and glial cells. Its expression is also upregulated in hepatocytes during regeneration and in lymphoid cells when they are signaled to proliferate. In this review, we summarize available data as rationale for the therapeutic manipulation of STMN1 in cancer patients.     

Stathmin and phospho-stathmin protein signature is associated with survival outcomes of breast cancer patients

Currently, Stathmin1 (STMN1) and phospho-STMN1 levels in breast cancers and their clinical implications are unknown. We examined the expression of STMN1 and its serine phospho-site (Ser16, Ser25, Ser38, and Ser63) status by immunohistochemistry. Using Cox regression analysis, a STMN1 expression signature and phosphorylation profile plus clinicopathological characteristics (STMN1-E/P/C) was developed in the training set (n = 204) and applied to the validation set (n = 106). This tool enabled us to separate breast cancer patients into high- and low-risk groups with significantly different disease-free survival (DFS) rates (P < 0.001). Importantly, this STMN1-E/P/C model had a greater prognostic value than the traditional TNM classifier, especially in luminal subtype breast cancer (P = 0.002). Further analysis showed that patients in the low-risk group would benefit more from adjuvant paclitaxel-based chemotherapy (P = 0.002). In conclusion, the STMN1-E/P/C signature is a reliable prognostic indicator for luminal subtype breast cancer and may predict the therapeutic response to paclitaxel-based treatments, potentially facilitating individualized management.     

微管不稳定蛋白在消化系肿瘤中的表达及意义

 由于微管不稳定蛋白特有的微管解聚活性,在细胞的增殖、分化及肿瘤的发生中起着重要的作用。近年来,微管不稳定蛋白在消化系肿瘤中的异常表达吸引了很多的关注。研究发现,微管不稳定蛋白的高表达与消化系肿瘤的分化程度,浸润深度,淋巴结转移或TNM分期等呈正相关。     

Stathmin: a protein with many tasks. New biomarker and potential target in cancer

Introduction: Stathmin is a microtubule-destabilizing phosphoprotein, firstly identified as the downstream target of many signal transduction pathways. Several studies then indicated that stathmin is overexpressed in many types of human malignancies, thus deserving the name of Oncoprotein 18 (Op18). At molecular level, stathmin depolymerizes microtubules by either sequestering free tubulin dimers or directly inducing microtubule-catastrophe. A crucial role for stathmin in the control of mitosis has been proposed, since both its overexpression and its downregulation induce failure in the correct completion of cell division. Accordingly, stathmin is an important target of the main regulator of M phase, cyclin-dependent kinase 1.

Areas covered: Recent evidences support a role for stathmin in the regulation of cell growth and motility, both in vitro and in vivo, and indicate its involvement in advanced, invasive and metastatic cancer more than in primary tumors.

Expert opinion: Many studies suggest that high stathmin expression levels in cancer negatively influence the response to microtubule-targeting drugs. These notions together with the fact that stathmin is expressed at very low levels in most adult tissues strongly support the use of stathmin as marker of prognosis and as target for novel anti-tumoral and anti-metastatic therapies.     

stathmin基因的表达与长春瑞滨治疗非小细胞肺癌疗效关系

背景与目的: 化疗是晚期非小细胞肺癌(NSCLC)的主要治疗手段,但是NSCLC常对化疗耐药,导致治疗失败.因此,针对不同分子生物学特点的NSCLC进行化疗疗效预测,成为提高疗效的重要方法.本研究通过研究晚期NSCLC患者肿瘤组织中Stathmin基因的表达与患者对长春碱类药物的化疗敏感性的关系,为患者选择适当的药物治疗提供依据.方法:2005年5月-2007年12月,共78例晚期NSCLC患者入组,随机分ANP方案[长春瑞滨(NVB)联合顺铂(DDP)或卡铂(CBP)]化疗组或GP方案[吉西他滨(GEM)联合DDP或CBP]化疗组,观察两组对化疗的反应;同时以RT-PCR法检测患者病理组织中Stathmin mRNA的表达,以Western印迹法检测Stathmin的蛋白含量.结果: NP组41N,GP组37例,两组患者的性别、年龄、病理类型及肿瘤分期等临床特点无显著性差异(P>0.05),对化疗总的有效率分别为46.3%(19/41)和48.6%(18/37),两者之间亦未见显著差异(P>0.05);在NP组内,有效19例,无效22例,有效患者的肿瘤组织中stathmin mRNA测量值为1.9±1.1,而无效患者为7.5±2.8,两者之间差异有显著性(P=0.003).有效患者的Stathmin蛋白测量值为1.5±0.7.无效组为4.3±1.6,两者之间差异有显著性(P=0.002).GP组18例有效,19例无效,有效与无效患者肿瘤组织中stathmin mRNA及Stathmin蛋白无明显差异(P>0.05). 结论: NSCLC患者肿瘤组织中stathmin基因的表达与患者对长春碱药物的敏感性有关,stathmin基因高表达,对长春碱药物的敏感性低,宜换用其他药物治疗.     

Stathmin levels in growth plate chondrocytes are modulated by vitamin D3 metabolites and transforming growth factor-beta1 and are associated with proliferation

Stathmin is a highly conserved, phosphorylated cytosolic protein that is found at decreased levels in all cells as they become more terminally differentiated, or when they decrease in their rate of proliferation. This study examined the hypothesis that stathmin levels in growth plate chondrocytes decreases as endochondral maturation increases. To test this hypothesis, we used a costochondral growth plate chondrocyte cell culture model. Cells derived from the resting zone (RC) express twice as much stathmin mRNA in culture and have twice as much stathmin protein as cells derived from the post proliferative growth zone ([GC];prehypertrophic and upper hypertrophic cell zones). Stathmin levels in vivo were assessed by immunohistochemistry. To assess the effects of agents that modulate proliferation and differentiation, RC and GC chondrocytes were cultured in the presence of 10⁻¹⁰ to 10⁻⁸ M 1α,25-(OH)₂D₃, which regulates proliferation in both cell types but affects differentiation of only GC cells, or 10⁻⁹ to 10⁻⁷ M 24R,25-(OH)₂D₃, which regulates differentiation and maturation of RC cells, but decreases proliferation of GC cells. In addition, RC cells were treated with 0.44 or 0.88 ng/mL of recombinant human transforming growth factor β1 (rhTGF-β1), which stimulates proliferation of RC cells and regulates proteoglycan production, but not alkaline phosphatase activity. Stathmin protein levels were determined using quantitative immunoblots, with recombinant human stathmin as a standard. The results show that stathmin levels are associated with proliferation. Proliferating chondrocytes in vivo exhibited higher levels of immunoreactive stathmin than either RC or GC cells in the growth plate. In culture, 1α,25-(OH)₂D₃ caused a dose-dependent de-crease in stathmin in RC and GC cells within 24 h. 24 R, 25-(OH)₂D₃ also reduced stathmin levels in GC cells within 24 h but only affected RC cells after prolonged exposures (96 h), at which time RC cells express a GC-like phenotype. rhTGF-β1 caused an increase in stathmin levels in RC cells. Stathmin levels are sensitive to protein kinase C (PKC) in other cells. Inhibition of PKC with chelerythrine had no effect on the response of RC cells to 1α,25-(OH)₂D₃ but it blocked the effect of rhTGF-β1, indicating that decreases in stathmin by vitamin D₃ metabolites may not be modulated by PKC, whereas increases in stathmin via rhTGF-β1 may be regulated via a PKC-dependent mechanism. These results support the hypothesis that constitutively expressed levels of stathmin are related to cell maturation state and that they are modulated by factors that regulate proliferation.     

Stathmin 1 RNA干扰载体的构建及功能检测

目的 构建用于stathmin 1 RNA干扰的重组质粒并验证其干扰效果,初步探讨stathmin 1 对于黑色素细胞生长的影响.方法 两步PCR法构建含有shRNA编码序列的重组质粒,脂质体转染黑色素细胞.RT-PCR、Western 印迹等方法检测stathmin 1在黑色素细胞中表达水平改变;MTT、流式细胞仪等方法检测黑色素细胞生长状态.结果 成功构建3个stathmin 1特异性的RNA干扰载体,在黑色素细胞中能有效降低stathmin 1在mRNA水平的表达,蛋白质表达水平分别降低为对照组的6 %、17 %和15 %;黑色素细胞的生长由于stathmin 1 减弱表达而受到明显抑制,凋亡率提高到约60 %.结论 干扰质粒能有效介导stathmin 1的RNA干扰;stathmin 1对于黑色素细胞的生长具有重要意义.     

Stathmin表达抑制的鼻咽癌细胞系建立

目的 建立stathmin表达抑制的鼻咽癌细胞系,为stathmin在鼻咽癌中的生物学功能研究提供实验基础.方法 合成stathmin特异性干扰DNA片段,将合成的干扰DNA片段克隆到siRNA质粒表达载体pGenesil-1.1,载体导入JM109菌株进行扩增,酶切和测序对重组表达载体进行鉴定.应用脂质体将质粒表达载体转入鼻咽癌5-8F细胞,采用G418进行筛选;RT-PCR和Western blot检测stathmin表达.结果 酶切和测序分析证实,插入siRNA质粒表达载体中的stathmin干扰DNA片段的序列和方向正确.表达分析表明,构建的stathmin特异性siRNA质粒表达载体能有效沉默stathmin在鼻咽癌5-8F细胞中的表达.结论 sathmin表达抑制的鼻咽癌细胞系建立成功.