FAM84B, amplified in pancreatic ductal adenocarcinoma, promotes tumorigenesis through the Wnt/β-catenin pathway
FAM84B, amplified in pancreatic ductal adenocarcinoma, promotes tumorigenesis through the Wnt/β-catenin pathway
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FAM84B 在胰腺导管腺癌中扩增，通过 Wnt/β-连环蛋白途径促进肿瘤发生
DOI：
10.18632/aging.103044
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发表时间：
2020-04-30
期刊：
影响因子：
5.2
通讯作者：
Yang, Dejun
中科院分区：
文献类型：
--
作者：
Zhang, Xin;Xu, Jiapeng;Yang, Dejun
具有序列相似性的家族成员84，成员B(FAM84B)的表达改变在多种人类癌症中被发现。然而，FAM84B在胰腺导管腺癌(PDAC)中的表达和功能尚未见报道。在这里，通过分析癌症基因组图谱队列，我们发现在141例PDAC患者中有11%的人观察到FAM84B扩增，并且FAM84B扩增与FAM84B基因的高表达相关。FAM84B扩增和过度表达与总生存率显著相关。此外，在PDAC细胞系中FAM84B基因的敲除抑制了细胞的增殖并诱导了细胞的凋亡。FAM84B基因敲除也抑制了线粒体！PDAC细胞的功能和糖酵解。有趣的是，FAM84B基因的敲除降低了β-连环蛋白的核积聚，降低了c-Myc和乳酸脱氢酶A的表达，但增强了Survivin的表达。相反，FAM84B过表达在细胞增殖、细胞凋亡、线粒体！功能和糖酵解，而糖酵解被Wnt/β-catenin途径抑制剂(XAV939)阻断。此外，无论在体内还是体外，FAM84B低表达的PDAC细胞对吉西他滨诱导的细胞增殖抑制都更加敏感。综上所述，FAM84B在PDAC的有氧糖酵解和肿瘤发生中起重要作用，Wnt/β-catenin可能参与了这一过程。
Altered expression of family with sequence similarity 84, member B (FAM84B) has been found in various human cancers. However, the expression and function of FAM84B in pancreatic ductal adenocarcinoma (PDAC) has not been studied. Here, by analyzing The Cancer Genome Atlas cohort, we found that FAM84B amplification was observed in 11% of 141 PDAC patients, and FAM84B amplification was correlated with higher mRNA expression of FAM84B. FAM84B amplification and overexpression was significantly correlated with poor overall survival. Moreover, knockdown of FAM84B in PDAC cell lines suppressed cell proliferation and induced apoptosis. FAM84B knockdown also suppressed mitochondria! function and glycolysis of PDAC cells. Interestingly, knockdown of FAM84B decreased the nuclear accumulation of beta-catenin, and the expression of c-Myc and lactate dehydrogenase A, but enhanced the expression of Survivin. On the contrary, FAM84B overexpression displayed reversed effects in cell proliferation, apoptosis, mitochondria! function, and glycolysis, which was blocked by the Wnt/beta-catenin pathway inhibitor (XAV939). In addition, PDAC cells with lower expression of FAM84B were more sensitive to gemcitabine-induced cell proliferation inhibition both in vitro and in vivo. In conclusion, FAM84B plays an important role in aerobic glycolysis and tumorigenesis in PDAC and Wnt/beta-catenin may be involved in this process.