LIMK与结直肠癌关系的研究进展

Research progress on relationship between LIMK and colorectal cancer

目的了解LIM激酶(LIMK)与结直肠癌的关系,为结直肠癌的转移、侵袭及靶向治疗提供研究依据。方法复习近年来国内外关于LIMK的结构功能以及其与结直肠癌关系研究进展的相关文献并加以综述。结果 LIMK及其主要通路ROCK/LIMK/cofilin及PAK/LIMK/cofilin上下游因子均参与了肿瘤细胞周期进展、肿瘤细胞侵袭、迁移、增殖等多种细胞生物学行为,如p21活化蛋白激酶4(PAK4)通过PAK4/LIMK1/cofilin信号通路参与细胞骨架动力学调节癌细胞迁移和侵袭,cofilin经过Rho/ROCK/LIMK1/cofilin通路影响肿瘤细胞运动和形态的变化,从而参与肿瘤细胞的侵袭和迁移;两种肿瘤转移相关蛋白MYH9和ACTN4为LIMK1的直接靶标,此三者相互作用可以促进结肠癌进展。LIMK家族的另一成员LIMK2可通过限制上皮间充质转化过程抑制细胞转移的能力,并与β-连环蛋白的核可激活Wnt信号传导途径,从而导致结肠癌进展和转移。二烯丙基二硫可以下调结肠癌细胞SW480中LIMK1的表达,抑制LIMK1/cofilin信号通路,阻碍血管生成和上皮间充质转化,抑制结肠癌的迁移和侵袭,而其他LIMK抑制剂暂未在结直肠癌中得到验证。结论结直肠癌及其转移的分子机制尚未完全阐明,通过对结直肠癌及其转移机制与LIMK关系的深入研究,可为结直肠癌及转移提供分子靶向治疗突破点,并有助于为探究结直肠癌的诊断、判断复发、预后及转移情况提供更多帮助。

Objective To understand relationship between LIM kinase(LIMK) and colorectal cancer in order to provide research basis for metastasis, invasion, and targeted therapy of colorectal cancer. Method The relevant literatures about the research progress on the structural function of LIMK and its correlation with colorectal cancer in recent years were reviewed. Results The LIMK and its factors in the ROCK/LIMK/cofilin and PAK/LIMK/cofilin pathways were involved in various cell biological behaviors such as the tumor cell cycle progression, tumor cell invasion,migration, and proliferation. For example, the p21-activated kinase 4(PAK4) participated in the cytoskeletal dynamics to regulate cancer cell migration and invasion through the PAK4/LIMK1/cofilin signaling pathway. The cofilin affected the tumor cell movement and morphology through the Rho/ROCK/LIMK1/cofilin signaling pathway, thus then participated in the tumor cell invasion and migration. In addition, the studies had reported that two tumor metastasis-associated proteins, MYH9 and ACTN4, were the direct targets of LIMK1, and the three interactions could promote the colon cancer progression. Another member of the LIMK family: LIMK2, which inhibited the cell metastasis by limiting the epithelial mesenchymal transition(EMT) process, and the nuclear chain of β-catenin activated the Wnt signaling pathway, leading to the colon cancer progression and metastasis. Diallyl disulfide down-regulated the expression of LIMK1 in the colon cancer cells SW480, inhibited the LIMK1/cofilin signaling pathway, blocked angiogenesis and EMT, and inhibited the colon cancer migration and invasion, while others LIMK inhibitors had not been validated in the colorectal cancer.Conclusions Molecular mechanism of colorectal cancer and its metastasis has not been fully elucidated. Through indepth study of relationships between colorectal cancer and its metastasis mechanism and LIMK, it could provide a molecular targeted therapeutic breakthrough for colorectal cancer and its metastasis and more help for exploring of diagnosis, recurrence, prognosis and metastasis of colorectal cancer.