ARNT-dependent CCR8 reprogrammed LDH isoform expression correlates with poor clinical outcomes of prostate cancer
ARNT-dependent CCR8 reprogrammed LDH isoform expression correlates with poor clinical outcomes of prostate cancer
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ARNT 依赖性 CCR8 重编程 LDH 亚型表达与前列腺癌不良临床结果相关
DOI：
10.1002/mc.23201
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发表时间：
2020-04-22
影响因子：
4.6
通讯作者：
Zhong, Wei-de
中科院分区：
文献类型：
--
作者：
Chen, Guo;Cai, Zhi-duan;Zhong, Wei-de
乳酸脱氢酶同工酶（LDH）是由LDHA和LDHB两种同工酶组成的四聚体，其表达与细胞代谢和癌症进展相关。本研究旨在探讨CC-趋化因子配体18（CCL 18）对前列腺癌（PCa）发生、发展的调控作用。结果表明，CCL 18在mRNA和蛋白水平均上调PCa细胞LDHA的表达，下调LDHB的表达。CCR 8的缺失降低了CCL 18促进PCa细胞增殖、迁移和乳酸产生的能力。CCR 8调节的转录因子ARNT的耗尽显著降低了LDHA的表达。此外，癌症基因组图谱数据集分析显示CCR 8和ARNT表达之间呈正相关。二维差示凝胶电泳显示PCa患者前列腺液和PCa组织中LDHA/LDHB比值均增高。此外，LDHA/LDHB比值增加与PCa患者的临床结局不良相关。总之，我们的研究结果表明，CCR 8途径以ARNT依赖性方式编程LDH亚型表达，并且LDHA/LDHB的比率具有作为PCa诊断和预后的生物标志物的潜力。
Lactate dehydrogenase isozyme (LDH) is a tetramer constituted of two isoforms, LDHA and LDHB, the expression of which is associated with cell metabolism and cancer progression. Our previous study reveals that CC-chemokine ligand-18 (CCL18) is involved in progression of prostate cancer (PCa).This study aims to investigate how CCL18 regulates LDH isoform expression, and therefore, contributes to PCa progression. The data revealed that the expression of LDHA was upregulated and LDHB was downregulated in PCa cells by CCL18 at both messenger RNA and protein levels. The depletion of CCR8 reduced the ability of CCL18 to promote the proliferation, migration, and lactate production of PCa cells. Depletion of a CCR8 regulated transcription factor, ARNT, significantly reduced the expression of LDHA. In addition, The Cancer Genome Atlas dataset analyses revealed a positive correlation between CCR8 and ARNT expression. Two dimension difference gel electrophoresis revealed that the LDHA/LDHB ratio was increased in the prostatic fluid of patients with PCa and PCa tissues. Furthermore, increased LDHA/LDHB ratio was associated with poor clinical outcomes of patients with PCa. Together, our results indicate that the CCR8 pathway programs LDH isoform expression in an ARNT dependent manner and that the ratio of LDHA/LDHB has the potential to serve as biomarkers for PCa diagnosis and prognosis.