Autophagy gene expression profiling identifies a defective microtubule-associated protein light chain 3A mutant in cancer.
Autophagy gene expression profiling identifies a defective microtubule-associated protein light chain 3A mutant in cancer.
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DOI：
10.18632/oncotarget.9754
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发表时间：
2016-07-05
期刊：
影响因子：
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通讯作者：
Ketteler R
中科院分区：
文献类型：
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作者：
Costa JR;Prak K;Aldous S;Gewinner CA;Ketteler R
细胞应激反应自噬与多种疾病有关，包括神经退行性变和癌症。自噬在癌症中的作用还不清楚，自噬促进肿瘤和抑制肿瘤的作用都已有报道，这使得基于自噬途径的治疗策略的设计变得复杂。在这里，我们系统地分析了47个自噬基因在各种癌症中的缺失、扩增和突变的基因表达数据。我们发现，一些癌症类型具有频繁的自噬基因扩增，而缺失在前列腺癌中更为常见。其他类型的癌症，如胶质母细胞瘤和甲状腺癌，47个自噬基因中的任何一个都几乎没有变化。总体而言，在癌症中，个体自噬核心基因的改变频率很低，这表明癌细胞需要功能性自噬。一些自噬基因表现出频繁的单碱基突变，例如ULK蛋白激酶家族的成员。此外，我们在MAP1LC3A富含精氨酸的区域发现了热点突变，导致MAP1LC3A在体外和体内被ATG4B切割减少，这表明该基因突变在癌症发生中具有一定的功能意义。
The cellular stress response autophagy has been implicated in various diseases including neuro-degeneration and cancer. The role of autophagy in cancer is not clearly understood and both tumour promoting and tumour suppressive effects of autophagy have been reported, which complicates the design of therapeutic strategies based on targeting the autophagy pathway. Here, we have systematically analyzed gene expression data for 47 autophagy genes for deletions, amplifications and mutations in various cancers. We found that several cancer types have frequent autophagy gene amplifications, whereas deletions are more frequent in prostate adenocarcinomas. Other cancer types such as glioblastoma and thyroid carcinoma show very few alterations in any of the 47 autophagy genes. Overall, individual autophagy core genes are altered at low frequency in cancer, suggesting that cancer cells require functional autophagy. Some autophagy genes show frequent single base mutations, such as members of the ULK family of protein kinases. Furthermore, we found hotspot mutations in the arginine-rich stretch in MAP1LC3A resulting in reduced cleavage of MAP1LC3A by ATG4B both in vitro and in vivo, suggesting a functional implication of this gene mutation in cancer development.