Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth.
Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth.
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DOI：
10.1038/s41388-020-01523-5
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发表时间：
2021-01
期刊：
影响因子：
8
通讯作者：
Han R
中科院分区：
文献类型：
--
作者：
Li H;Zhao L;Lau YS;Zhang C;Han R
在美国，结直肠癌是癌症相关死亡的第三大原因，也是男性和女性最常见的第三种癌症。大约20%的结肠癌病例与结肠炎密切相关。环境和遗传因素都被认为是结肠炎和肿瘤发生的原因。然而，调节结肠炎和结肠肿瘤发生的遗传因素仍然难以捉摸。由于活性氧物种(ROS)在组织炎症和肿瘤发生中起着至关重要的作用，在这里，我们采用全基因组CRISPR基因敲除筛选的方法来系统地识别参与氧化应激调节的遗传因素。下一代测序(NGS)显示，包括针对LGALS2的gRNA在内的600多个gRNA在亚致死性H_2O_2攻击后存活的细胞中高度浓缩。LGALS2编码糖链结合蛋白Galectin 2(Galectin 2)，Galectin 2主要在胃肠道表达，在人结肠肿瘤中表达下调。为了研究Gal2在结肠炎中的作用，我们采用了葡聚糖硫酸钠(DSS)诱导的有(WT)或不有(Gal2-KO)的小鼠急性结肠炎模型，结果表明Gal2缺乏改善了DSS诱导的结肠炎。我们进一步证明，使用偶氮甲烷(AOM)/葡聚糖硫酸钠(DSS)诱导的结直肠癌模型，Gal2-KO小鼠比WT小鼠发展出明显更大的肿瘤。我们发现，与WT小鼠相比，Gal2缺陷肿瘤中STAT3的磷酸化水平显著增加。Gal2过表达降低了人结肠肿瘤上皮细胞的增殖，并钝化了过氧化氢诱导的STAT3磷酸化。总体而言，我们的结果表明Gal2在结肠癌生长中发挥抑制作用，并突出了Gal2在结肠癌中的治疗潜力。
Colorectal cancer is the third leading cause of cancer-related deaths in the United States and the third most common cancer in men and women. Around 20% colon cancer cases are closely linked with colitis. Both environmental and genetic factors are thought to contribute to colon inflammation and tumor development. However, the genetic factors regulating colitis and colon tumorigenesis remain elusive. Since reactive oxygen species (ROS) is vitally involved in tissue inflammation and tumorigenesis, here we employed a genome-wide CRISPR knockout screening approach to systemically identify the genetic factors involved in the regulation of oxidative stress. Next generation sequencing (NGS) showed that over 600 gRNAs including the ones targeting LGALS2 were highly enriched in cells survived after sublethal H2O2 challenge. LGALS2 encodes the glycan-binding protein Galectin 2 (Gal2), which is predominantly expressed in the gastrointestinal tract and downregulated in human colon tumors. To examine the role of Gal2 in colitis, we employed the dextran sodium sulfate (DSS)-induced acute colitis model in mice with (WT) or without Lgals2 (Gal2-KO) and showed that Gal2 deficiency ameliorated DSS-induced colitis. We further demonstrated that Gal2-KO mice developed significantly larger tumors than WT mice using Azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal cancer model. We found that STAT3 phosphorylation was significantly increased in Gal2-deficient tumors as compared to those in WT mice. Gal2 overexpression decreased the proliferation of human colon tumor epithelial cells and blunted H2O2-induced STAT3 phosphorylation. Overall, our results demonstrate that Gal2 plays a suppressive role in colon tumor growth and highlights the therapeutic potential of Gal2 in colon cancer.
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影响因子：
16.6
作者：
Aran D;Camarda R;Odegaard J;Paik H;Oskotsky B;Krings G;Goga A;Sirota M;Butte AJ
通讯作者：
Butte AJ
影响因子：
8.8
作者：
Han J;Perez JT;Chen C;Li Y;Benitez A;Kandasamy M;Lee Y;Andrade J;tenOever B;Manicassamy B
通讯作者：
Manicassamy B
影响因子：
--
作者：
Diniz TC;Silva JC;de Lima-Saraiva SR;Ribeiro FP;Pacheco AG;de Freitas RM;Quintans-Júnior LJ;Quintans Jde S;Mendes RL;Almeida JR
通讯作者：
Almeida JR
VCP/p97 通过加速泛素连接酶 Smurf1 降解来增强 BMP 信号传导
影响因子：
4.8
作者：
Li, Haiwen;Cui, Yu;Zhang, Lingqiang
通讯作者：
Zhang, Lingqiang
影响因子：
46.9
作者：
Morgens DW;Deans RM;Li A;Bassik MC
通讯作者：
Bassik MC