Targeting hypoxia regulated sodium driven bicarbonate transporters reduces triple negative breast cancer metastasis.
Targeting hypoxia regulated sodium driven bicarbonate transporters reduces triple negative breast cancer metastasis.
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DOI：
10.1016/j.neo.2022.01.003
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
McIntyre A
中科院分区：
文献类型：
--
作者：
Carroll CP;Bolland H;Vancauwenberghe E;Collier P;Ritchie AA;Clarke PA;Grabowska AM;Harris AL;McIntyre A
低氧（缺氧）区域存在于超过 50% 的乳腺肿瘤中，最常见于更具侵袭性的三阴性乳腺癌亚型 (TNBC)。转移是 90% 乳腺癌患者死亡的原因。肿瘤缺氧区域往往呈酸性，缺氧和酸中毒都会增加肿瘤转移。与此相符，转移过程依赖于 pH 调节机制。我们和其他人之前已经发现 Na+ 驱动的碳酸氢盐转运蛋白 (NDBT) 的缺氧表达增加是肿瘤 pH 调节的主要机制。缺氧诱导 TNBC 中 NDBT 的表达，最常见的是 SLC4A4 和 SLC4A5。 NDBT 抑制 (S0859) 和 shRNA 敲低可抑制体外迁移（减少 40%）和侵袭（减少 70%）。 NDBT 敲低显着减少了体内肿瘤异种移植转移。为了研究 NDBT 支持转移的机制，我们研究了它们在磷酸信号传导、上皮间质转化 (EMT) 和代谢调节中的作用。 NDBT 敲低导致缺氧磷酸信号激活减弱；最值得注意的是 LYN (Y397) 减少了 75%，LCK (Y394) 减少了 72%。转移过程与 EMT 相关。我们发现 NDBT 敲低会抑制 EMT，调节关键 EMT 转录因子的表达并消除波形蛋白的表达，同时增加 E-钙粘蛋白的表达。 NDBT 敲低还改变了代谢活动，降低了总体 ATP 和细胞外乳酸水平。这些结果表明，靶向缺氧诱导的 NDBT 可作为调节磷酸信号传导、EMT 和代谢活性并减少肿瘤体内迁移、侵袭和转移的方法。
Regions of low oxygen (hypoxia) are found in >50% of breast tumours, most frequently in the more aggressive triple negative breast cancer subtype (TNBC). Metastasis is the cause of 90% of breast cancer patient deaths. Regions of tumour hypoxia tend to be more acidic and both hypoxia and acidosis increase tumour metastasis. In line with this the metastatic process is dependent on pH regulatory mechanisms. We and others have previously identified increased hypoxic expression of Na+ driven bicarbonate transporters (NDBTs) as a major mechanism of tumour pH regulation. Hypoxia induced the expression of NDBTs in TNBC, most frequently SLC4A4 and SLC4A5. NDBT inhibition (S0859) and shRNA knockdown suppressed migration (40% reduction) and invasion (70% reduction) in vitro. Tumour xenograft metastasis in vivo was significantly reduced by NDBT knockdown. To investigate the mechanism by which NDBTs support metastasis, we investigated their role in regulation of phospho-signalling, epithelial-to-mesenchymal transition (EMT) and metabolism. NDBT knockdown resulted in an attenuation in hypoxic phospho-signalling activation; most notably LYN (Y397) reduced by 75%, and LCK (Y394) by 72%. The metastatic process is associated with EMT. We showed that NDBT knockdown inhibited EMT, modulating the expression of key EMT transcription factors and ablating the expression of vimentin whilst increasing the expression of E-cadherin. NDBT knockdown also altered metabolic activity reducing overall ATP and extracellular lactate levels. These results demonstrate that targeting hypoxia-induced NDBT can be used as an approach to modulate phospho-signalling, EMT, and metabolic activity and reduce tumour migration, invasion, and metastasis in vivo.
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影响因子：
3.5
作者：
Groeger, Nicole;Vitzthum, Helga;Boettger, Thomas
通讯作者：
Boettger, Thomas
影响因子：
6.4
作者：
Boedtkjer, Ebbe;Moreira, Jose M. A.;Aalkjaer, Christian
通讯作者：
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影响因子：
10.8
作者：
Boedtkjer, Ebbe;Bentzon, Jacob F.;Aalkjaer, Christian
通讯作者：
Aalkjaer, Christian
DOI：
10.1007/978-94-007-7359-2_11
发表时间：
2014-01-01
期刊：
CARBONIC ANHYDRASE: MECHANISM, REGULATION, LINKS TO DISEASE, AND INDUSTRIAL APPLICATIONS
影响因子：
--
作者：
Benej, Martin;Pastorekova, Silvia;Pastorek, Jaromir
通讯作者：
Pastorek, Jaromir
影响因子：
4.5
作者：
Chen JL;Lucas JE;Schroeder T;Mori S;Wu J;Nevins J;Dewhirst M;West M;Chi JT
通讯作者：
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