Rac GTPase activating protein 1 promotes gallbladder cancer via binding DNA ligase 3 to reduce apoptosis.
Rac GTPase activating protein 1 promotes gallbladder cancer via binding DNA ligase 3 to reduce apoptosis.
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DOI：
10.7150/ijbs.58857
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发表时间：
2021
影响因子：
9.2
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Bian R;Dang W;Song X;Liu L;Jiang C;Yang Y;Li Y;Li L;Li X;Hu Y;Bao R;Liu Y
Rac GTPase激活蛋白1 （RACGAP1）已被认为与多种恶性肿瘤的发病和进展有关，但其在胆囊癌（GBC）发展中的作用尚不清楚。本研究旨在描述RACGAP1在GBC中的作用及其相关的分子机制。研究发现，RACGAP1在人GBC组织中高表达，与较差的总生存期（OS）相关。在体外和体内实验中，敲低RACGAP1基因可抑制肿瘤细胞的增殖和存活。我们进一步发现，RACGAP1通过与DNA连接酶3 （LIG3）的结合参与DNA修复，而LIG3是选择性非同源末端连接（Alt-NHEJ）途径的关键组成部分。RACGAP1独立于RhoA活性调节LIG3的表达。RACGAP1敲低导致lig3依赖性修复功能障碍、DNA损伤积累和聚（adp -核糖基）修饰（PARylation）增强，导致细胞凋亡增加和细胞生长抑制。我们得出结论，RACGAP1通过结合LIG3在GBC中发挥促瘤作用，减少细胞凋亡，促进细胞生长，提示RACGAP1可能是GBC的潜在治疗靶点。
Rac GTPase activating protein 1 (RACGAP1) has been characterized in the pathogenesis and progression of several malignancies, however, little is known regarding its role in the development of gallbladder cancer (GBC). This investigation seeks to describe the role of RACGAP1 and its associated molecular mechanisms in GBC. It was found that RACGAP1 was highly expressed in human GBC tissues, which was associated to poorer overall survival (OS). Gene knockdown of RACGAP1 hindered tumor cell proliferation and survival both in vitro and in vivo. We further identified that RACGAP1 was involved in DNA repair through its binding with DNA ligase 3 (LIG3), a crucial component of the alternative-non-homologous end joining (Alt-NHEJ) pathway. RACGAP1 regulated LIG3 expression independent of RhoA activity. RACGAP1 knockdown resulted in LIG3-dependent repair dysfunction, accumulated DNA damage and Poly(ADP-ribosyl) modification (PARylation) enhancement, leading to increased apoptosis and suppressed cell growth. We conclude that RACGAP1 exerts a tumor-promoting role via binding LIG3 to reduce apoptosis and facilitate cell growth in GBC, pointing to RACGAP1 as a potential therapeutic target for GBC.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
11.4
作者：
Hu Y;Lin J;Fang H;Fang J;Li C;Chen W;Liu S;Ondrejka S;Gong Z;Reu F;Maciejewski J;Yi Q;Zhao JJ
通讯作者：
Zhao JJ
DOI：
10.1083/jcb.201204107
发表时间：
2012-09-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bastos RN;Penate X;Bates M;Hammond D;Barr FA
通讯作者：
Barr FA
影响因子：
2.6
作者：
Conci, Simone;Ruzzenente, Andrea;Scarpa, Aldo
通讯作者：
Scarpa, Aldo
影响因子：
4.8
作者：
Boulares, AH;Yakovlev, AG;Smulson, M
通讯作者：
Smulson, M