世界肿瘤研究  >> Vol. 8 No. 2 (April 2018)

LRRC超家族成员在肿瘤的研究进展
The Progress of Research on LRRC Super Family Members in Cancer

DOI: 10.12677/WJCR.2018.82013, PDF, HTML, XML, 下载: 797  浏览: 2,083  科研立项经费支持

作者: 史婧怡, 陈妍珂*:西安交通大学医学部,陕西 西安

关键词: 富亮氨酸重复序列(LRR)肿瘤Leucine Rich Repeat Sequence (LRR) Cancer

摘要: 富亮氨酸重复序列(LRR)存在于多种蛋白质中,介导多种蛋白与蛋白之间的相互作用。近年来一些研究发现:LRRC超家族成员LRRC4、LRRC3B和LG11在多种肿瘤组织表达缺失或显著降低,并具有抑癌基因的功能;而另外一些LRRC超家族成员LGR4和LGR5在肿瘤中高表达,表现出原癌基因的作用。以上研究提示它们可能成为肿瘤诊断和治疗的新靶点。本文就LRRC超家族成员在肿瘤的研究进展进行回顾性综述。
Abstract: The leucine rich repeat sequence (LRR) domains are known to mediate protein-protein interactions. In recent years, some studies have found that members of the LRRC super family (for example LRRC4, LRRC3B and LG11) were absent or significantly down-expressed in a variety of tumor tissue, and have the potential of suppressing tumorigenesis and tumor cell proliferation. LGR4 and LGR5 are up-expression in tumor, and show the function of proto-oncogene. These findings suggested that members of the LRRC super family may become the new target for diagnosis and treatment of tumor. In the present review we summarize the current literature about LRRC super family in the cancer.

文章引用: 史婧怡, 陈妍珂. LRRC超家族成员在肿瘤的研究进展[J]. 世界肿瘤研究, 2018, 8(2): 81-85. https://doi.org/10.12677/WJCR.2018.82013

1. 引言

富亮氨酸重复(1eucine rich repeat, LRR)序列存在于多种蛋白质中,1985年由Takahashi等从人血清糖蛋白中首次发现 [1] ,因亮氨酸残基在该结构中呈规律性排列而将其命名为LRR。富含LRR基序的蛋白(Leucinerich repeat containing protein, LRRC)广泛分布于胞浆、胞膜、细胞核和细胞外基质中,组成了进化上保守、功能多样的LRRC超家族。目前发现其成员已多达4000多种,包括细胞黏附分子、核糖核酸酶抑制剂、酪氨酸激酶受体、细胞外基质糖蛋白及病毒因子等,它们参与生物体的多种功能,如细胞的黏附、极性分化及胞内转运、基因的表达调控、激素与受体的相互作用和神经系统的发育等 [2] 。

2. LRR基序的结构特征

该结构域通常由20~29个氨基酸残基组成,其中包含一段长度为11个残基的保守序列LxxLxLxxN/CxL,其中x代表任意氨基酸,L可以被缬氨酸、异亮氨酸或苯丙氨酸取代 [3] 。Kobe和Deisenhofer研究发现,每个LRR基序由一个保守的β-片层和一个变化的α-螺旋通过loop环连接形成,相邻的多个LRR通常围绕共同的轴平行排列,形成一个卷曲的马蹄形结构。在这种结构中,β-片层与配体相结合形成一个疏水性核心,而α-螺旋则暴露在马蹄形结构的外周。当配体与受体结合时,其马蹄形结构发生改变 [3] [4] [5] 。因此,LRR结构域介导多种蛋白与蛋白之间的相互作用。

3. 具有抑癌基因性质的LRRC超家族成员

以往的研究发现:在头颈部肿瘤、乳腺癌、结直肠癌、卵巢癌及前列腺癌等多种恶性肿瘤中染色体7q31-32区和10q23-26区存在多个位点等位基因杂合性丢失(Loss of heterozygosity, LOH)和基因重排现象,提示该区域可能存在多个与恶性肿瘤发生和进展相关的基因 [6] - [11] 。王杰如等人运用EST介导的定位候选克隆技术从7q31-32区克隆出一个LRR超家族成员LRRC4 [12] 。张秋红等人的研究发现LRRC4在正常人脑组织中特异性表达,而在多种原发性脑瘤中表达明显下调甚至缺失,且其表达水平与脑胶质瘤的病理分级密切负相关 [13] 。在胶质母细胞瘤U251细胞过表达LRRC4显著抑制肿瘤细胞的成瘤能力和生长 [14] 。LRRC4主要通过阻断ERK/MAPK信号通路,下调Cyclin E和Cyclin A周期素的表达,抑制CDK2激酶的活性,上调p21wafi/Cip1和p27Kip1的表达,将细胞周期阻断在G1期。同时,LRRC4通过抑制PCNA抑制DNA复制,最终抑制胶质瘤细胞的增殖和成瘤 [13] [15] 。LRRC4还可以通过抑制SDF-1α/CXCR4生物学轴而减弱U251细胞的侵袭运动能力 [16] 。LRR结构域缺失的突变体不再抑制U251细胞的生长和侵袭;而Ig2或Tm区缺失的突变体仍然可以抑制U251细胞的生长和侵袭。该结果表明,LRRC4抑制U251细胞的生长和侵袭依赖于它的LRR结构域,而不是IgC2或Tm结构域 [15] 。

Chemova等人采用定位克隆技术也从染色体10q24区克隆到LRRC超家族另外一个成员LGll (1eucine-rich glioma inactivated1) [11] 。研究发现,LGll主要分布于正常神经系统组织,在恶性胶质瘤中由于基因重排其表达明显下调甚至缺失 [17] 。将LGll基因转入不表达内源性LGll的胶质瘤细胞系T98G和A172中,结果发现LGll基因的再表达显著抑制细胞的增殖和侵袭 [18] 。通过人类癌症微阵列分层研究比较肿瘤组织与正常组织基因表达谱,一些研究发现LRRC超家族另一个成员LRRC3B在人类乳腺癌 [19] 、胶质瘤 [20] 、结肠癌 [21] 、前列腺癌 [22] 、胃癌 [23] 及肺癌 [24] 中表达显著下调。将LRRC3B过表达质粒转染至人胃癌细胞中,观察到LRRC3B可抑制癌细胞集落形成 [25] 。

以上研究结果表明,部分LRRC超家族成员在肿瘤组织表达显著降低。究其原因,除了基因杂合性丢失和基因重排外,还可能与启动子区过度甲基化修饰有关。LRRC4的启动子在表达缺失的SFl26和SF767细胞存在完全的甲基化,采用去甲基化制剂5-Aza—CdR处理后,LRRC4表达显著上调 [26] 。

4. 具有原癌基因性质的LRRC家族成员

以上LRRC分子都表现出抑制肿瘤生长和侵袭的作用,由此可以推测LRRC超家族成员都具有抑癌基因的性质吗?最近几年,陆续有研究报道LRRC超家族成员在肿瘤中的作用不是如此简单。LGR4 (leucine-rich repeat domain containing G protein-coupled receptor 4)被发现在多种肿瘤中表达失调,它通过激活Jmjd2a/AR信号通路抑制前列腺癌细胞凋亡 [27] 。LGR5也被报道在肝癌 [28] 、胃癌 [29] 、基底细胞癌 [30] 、结肠癌和卵巢癌 [31] 中表达升高。过表达LGR5促进肿瘤细胞增殖 [30] ,而沉默其表达诱导肿瘤细胞凋亡 [29] 。

5. 小结和展望

综上所述,LRRC超家族成员在不同类型的恶性肿瘤中,其表达特点和作用都存在差异,提示LRRC超家族成员作用的复杂性。由于LRR结构域参与细胞内多种蛋白相互作用,因此推测LRRC超家族成员可能通过蛋白互作调控肿瘤细胞的生长和侵袭转移。深入研究该家族成员在肿瘤发生和进展中的作用和机制,有助于发展新的肿瘤标志物和靶向治疗分子,为肿瘤的诊断和治疗提供新的思路。

致谢

陕西省国际科技合作与交流计划面上项目(编号:2017KW-059)和西安交通大学本科生创新实验资助项目(编号:XJ201610698177)资助。

NOTES

*通讯作者。

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