B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2
B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2
复制标题
B7-H3 通过调节 HK2 促进结直肠癌细胞的有氧糖酵解和化疗耐药性。
DOI：
10.1038/s41419-019-1549-6
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发表时间：
2019-04-05
影响因子：
9
通讯作者：
Zhang, Xueguang
中科院分区：
文献类型：
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作者：
Shi, Tongguo;Ma, Yanchao;Zhang, Xueguang
越来越多的证据表明有氧糖酵解对结直肠癌（CRC）的发展很重要。然而，其潜在机制尚未阐明。B7-H3是一种免疫调节蛋白，在多种肿瘤类型中广泛过表达，在肿瘤进展中起着至关重要的作用。在这项研究中，我们发现B7-H3的过表达有效地增加了葡萄糖消耗和乳酸产生的速率，而B7-H3的敲低则具有相反的效果。此外，我们发现B7-H3通过促进CRC细胞中己糖激酶2（HK 2）的表达来增加葡萄糖消耗和乳酸产生，并且我们还发现HK 2是B7-H3诱导的CRC化学抗性的关键介质。HK 2表达的缺失或用HK 2抑制剂处理细胞可以逆转B7-H3诱导的有氧糖酵解增加和B7-H3赋予的癌细胞的化学抗性。此外，我们证实了B7-H3和HK 2在CRC患者的肿瘤组织中的表达之间的正相关性。总的来说，我们的研究结果表明，B7-H3可能是一种新的葡萄糖代谢和化疗耐药性的调节剂，通过控制大肠癌细胞中HK 2的表达，这一结果可能有助于开发B7-H3作为一个有前途的治疗目标，为大肠癌治疗。
Accumulating evidence suggests that aerobic glycolysis is important for colorectal cancer (CRC) development. However, the underlying mechanisms have yet to be elucidated. B7-H3, an immunoregulatory protein, is broadly overexpressed by multiple tumor types and plays a vital role in tumor progression. In this study, we found that overexpression of B7-H3 effectively increased the rate of glucose consumption and lactate production, whereas knockdown of B7-H3 had the opposite effect. Furthermore, we showed that B7-H3 increased glucose consumption and lactate production by promoting hexokinase 2 (HK2) expression in CRC cells, and we also found that HK2 was a key mediator of B7-H3-induced CRC chemoresistance. Depletion of HK2 expression or treating cells with HK2 inhibitors could reverse the B7-H3-induced increase in aerobic glycolysis and B7-H3-endowed chemoresistance of cancer cells. Moreover, we verified a positive correlation between the expression of B7-H3 and HK2 in tumor tissues of CRC patients. Collectively, our findings suggest that B7-H3 may be a novel regulator of glucose metabolism and chemoresistance via controlling HK2 expression in CRC cells, a result that could help develop B7-H3 as a promising therapeutic target for CRC treatment.