Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer.
Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer.
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DOI：
10.18632/oncotarget.9760
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发表时间：
2017-08-22
期刊：
影响因子：
--
通讯作者：
Yeh JJ
中科院分区：
文献类型：
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作者：
Anderson M;Marayati R;Moffitt R;Yeh JJ
胰腺导管腺癌是一种KRAS相关癌，转移率高，预后差。之前在PDAC基因工程小鼠模型中的工作表明，葡萄糖代谢对维持肿瘤生长非常重要。包括己糖激酶2(HK2)在内的多种糖酵解酶在原发性PDAC患者肿瘤中表达上调，支持糖酵解在促进人类疾病中的作用。HK2在PDAC转移瘤中的表达最高，提示HK2与侵袭性肿瘤生物学行为有关。为了支持这一点，我们发现在接受根治性手术的PDAC患者中，HK2的表达与较短的总生存期有关。在原代PDAC细胞系中，HK2的瞬时和稳定的敲除减少了乳酸的产生、锚定非依赖性生长(AIG)和通过重组基质的侵袭。反之，HK2的稳定过表达增加了乳酸的产生、细胞增殖、AIG和侵袭力。药物抑制乳酸的产生减少了HK2驱动的侵袭性增加，而添加细胞外乳酸则增强了侵袭性，共同提供了糖酵解活性和转移潜力之间的联系。尾静脉注射后，稳定的HK2基因敲除减少了异种细胞系中原发肿瘤的生长，降低了肺转移的发生率。HK2表达降低的肿瘤的基因表达分析显示，作为血管生成和转移重要途径的VEGF-A信号发生了变化，这与HK2促进转移的要求是一致的。总体而言，我们的数据为HK2在促进PDAC疾病进展中的作用提供了强有力的证据，表明直接抑制HK2可能是一种在临床上有前景的方法。
Pancreatic ductal adenocarcinoma (PDAC) is a KRAS-driven cancer with a high incidence of metastasis and an overall poor prognosis. Previous work in a genetically engineered mouse model of PDAC showed glucose metabolism to be important for maintaining tumor growth. Multiple glycolytic enzymes, including hexokinase 2 (HK2), were upregulated in primary PDAC patient tumors, supporting a role for glycolysis in promoting human disease. HK2 was most highly expressed in PDAC metastases, suggesting a link between HK2 and aggressive tumor biology. In support of this we found HK2 expression to be associated with shorter overall survival in PDAC patients undergoing curative surgery. Transient and stable knockdown of HK2 in primary PDAC cell lines decreased lactate production, anchorage independent growth (AIG) and invasion through a reconstituted matrix. Conversely, stable overexpression of HK2 increased lactate production, cell proliferation, AIG and invasion. Pharmacologic inhibition of lactate production reduced the HK2-driven increase in invasion while addition of extracellular lactate enhanced invasion, together providing a link between glycolytic activity and metastatic potential. Stable knockdown of HK2 decreased primary tumor growth in cell line xenografts and decreased incidence of lung metastasis after tail vein injection. Gene expression analysis of tumors with decreased HK2 expression showed alterations in VEGF-A signaling, a pathway important for angiogenesis and metastasis, consistent with a requirement of HK2 in promoting metastasis. Overall our data provides strong evidence for the role of HK2 in promoting PDAC disease progression, suggesting that direct inhibition of HK2 may be a promising approach in the clinic.