Research for molecular mechanism and clinical application of calponin-gene therapy against Peritoneal dissemination of ovarian cancer

目的：钙调蛋白h1（Calponin h1，CNh 1）是肌动蛋白结合蛋白家族的成员之一，它稳定肌动蛋白丝并调节多种细胞生物学表型。近年来的研究表明，肿瘤的侵袭性扩散与周围基质细胞CNh 1和α-平滑肌肌动蛋白（α-SMA）表达的减少密切相关。本研究的目的是评价腹腔注射CNh 1基因治疗对卵巢癌腹膜播散的疗效。实验设计：我们使用腺病毒载体将CNh 1基因导入腹膜细胞和卵巢癌细胞，作为增强或诱导α-SMA和CNh 1表达的手段。通过体外细胞培养和体内动物实验检测了基因转染的效果。结果：在每个转染的细胞系中观察到形成更长和更粗的肌动蛋白纤维，并且这些纤维的定位与外部转导的CIVh 1的相一致。相对于 ...更多信息 通过细胞行为的改变，CNh 1转染的腹膜细胞获得了抵抗卵巢癌诱导的细胞形状收缩的能力，从而抑制了癌细胞通过单层腹膜细胞的侵袭。此外，CNh 1转染的卵巢癌细胞表现出抑制锚定非依赖性生长和侵袭性，后者伴随着受损的细胞运动。伴随的将CNh 1转染到腹膜细胞和卵巢癌细胞两者中产生了关于癌细胞通过腹膜细胞单层侵袭的附加抑制作用。腹腔注射CNh 1-腺病毒后，我们发现CNh 1-腺病毒成功地阻断了肿瘤诱导的腹膜细胞表面的形态学改变，并显著延长了荷瘤小鼠的生存时间。此外，CNH 1-腺病毒可以成功地提高抗癌药物的治疗效果，而不会增加副作用.Conclusions：因此，CNH 1-基因治疗对卵巢癌的腹膜播散是bifunctionally有效的，即通过抑制感染的腹膜细胞层，抑制癌症的侵袭，第二，通过直接的抗肿瘤作用对癌细胞的侵袭和生长特性。少

Purpose : Calponin h1 (CNh1), one of the family of actin-binding proteins, stabilizes the filaments of actin and modulates various cellular biological phenotypes. Recent studies revealed the close correlation between the invasive tumor spread and the reduced expression of CNh1 and alpha-smooth muscle actin (α-SMA) in the surrounding stromal cells. The purpose of this study is to evaluate the efficacy of intraperitoneal CNh1-gene therapy against peritoneal dissemination of ovarian cancer.Experimental Design : We used an adenoviral vector to induce the CNh1 gene into peritoneal cells and ovarian cancer cells, as a means of enhancing or inducing the expression of α-SMA as well as CNh1. The efficacy of gene transfer was examined by in vitro cell culture and in vivo animal experiments.Results : The formation of longer and thicker actin fibers was observed in each transfected cell line, and the localization of these fibers coincided with that of externally transducted CIVh1. With respect to … More changes in cell behavior, the CNh1-transfected peritoneal cells acquired an ability to resist ovarian cancer-induced shrinkage in cell shape, and thus cancer cell invasion through the monolayer of peritoneal cells was inhibited. In addition, CNh1-transfected ovarian cancer cells showed suppressed anchorage-independent growth and invasiveness, the latter of which accompanied impaired cell motility. The concomitant CNh1 transfection into both peritoneal cells and ovarian cancer cells produced an additive inhibitory effect with respect to cancer cell invasion through the peritoneal cell monolayer.By in vivo experiments designed to treat nude mice that had been intraperitoneally (i.p.) inoculated with ovarian cancer cells, we found that the i.p.injected CNh1-adenovirus successfully blocked cancer-induced morphological changes in peritoneal cell surface, and significantly prolonged the survival time of tumor-bearing mice. Moreover, CNh1-adenovirus could successfully enhance the therapeutic effect of an anticancer drug without increase in side effects.Conclusions : Thus CNh1-gene therapy against peritoneal dissemination of ovarian cancer is bifuctionally effective, ie through inhibitory effects on the infected peritoneal cell layers which suppress cancer invasion and, second, through direct anti-tumor effects against invasion and growth properties of cancer cells. Less