Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
FASEB J. 2010 Nov;24(11):4291-301. doi: 10.1096/fj.10-159970. Epub 2010 Jun 21.
Thymosin β4 (Tβ4) is an actin-binding peptide overexpressed in several tumors, including colon carcinomas. The aim of this study was to investigate the role of Tβ4 in promoting the tumorigenic properties of colorectal cancer stem cells (CR-CSCs), which are responsible for tumor initiation and growth. We first found that CR-CSCs from different patients have higher Tβ4 levels than normal epithelial cells. Then, we used a lentiviral strategy to down-regulate Tβ4 expression in CR-CSCs and analyzed the effects of such modulation on proliferation, survival, and tumorigenic activity of CR-CSCs. Empty vector-transduced CR-CSCs were used as a control. Targeting of the Tβ4 produced CR-CSCs with a lower capacity to grow and migrate in culture and, interestingly, reduced tumor size and aggressiveness of CR-CSC-based xenografts in mice. Moreover, such loss in tumorigenic activity was accompanied by a significant increase of phosphatase and tensin homologue (PTEN) and a concomitant reduction of the integrin-linked kinase (ILK) expression, which resulted in a decreased activation of protein kinase B (Akt). Accordingly, exogenous expression of an active form of Akt rescued all the protumoral features lost after Tβ4 targeting in CR-CSCs. In conclusion, Tβ4 may have important implications for therapeutic intervention for treatment of human colon carcinoma.
胸腺素 β4（Tβ4）是一种在多种肿瘤中过度表达的肌动蛋白结合肽，包括结肠癌。本研究旨在研究 Tβ4 在促进结直肠癌症干细胞（CR-CSCs）致瘤特性中的作用，CR-CSCs 是肿瘤起始和生长的原因。我们首先发现，来自不同患者的 CR-CSCs 的 Tβ4 水平高于正常上皮细胞。然后，我们使用慢病毒策略下调 CR-CSCs 中的 Tβ4 表达，并分析这种调节对 CR-CSCs 的增殖、存活和致瘤活性的影响。空载体转导的 CR-CSCs 用作对照。靶向 Tβ4 产生的 CR-CSCs 在培养中生长和迁移的能力较低，有趣的是，降低了基于 CR-CSC 的异种移植物在小鼠中的肿瘤大小和侵袭性。此外，这种致瘤活性的丧失伴随着磷酸酶和张力蛋白同源物（PTEN）的显著增加和整合素连接激酶（ILK）表达的同时减少，导致蛋白激酶 B（Akt）的激活减少。因此，外源性表达活性形式的 Akt 挽救了在 CR-CSCs 中靶向 Tβ4 后失去的所有促肿瘤特征。总之，Tβ4 可能对人类结肠癌的治疗干预具有重要意义。
