Contribution of Na+,HCO3--cotransport to cellular pH control in human breast cancer: A role for the breast cancer susceptibility locus NBCn1 (SLC4A7)
Contribution of Na+,HCO3--cotransport to cellular pH control in human breast cancer: A role for the breast cancer susceptibility locus NBCn1 (SLC4A7)
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DOI：
10.1002/ijc.27782
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发表时间：
2013-03-15
影响因子：
6.4
通讯作者：
Aalkjaer, Christian
中科院分区：
文献类型：
--
作者：
Boedtkjer, Ebbe;Moreira, Jose M. A.;Aalkjaer, Christian
最近的全基因组关联研究将Na+，HCO3-共转运体NBCn1 （SLC4A7）位点与乳腺癌易感性联系起来，但缺乏功能见解。为了确定NBCn1是否通过将HCO3-转运到细胞中来处理在高代谢活动中产生的酸，我们研究了NBCn1的表达以及Na+，HCO3-共转运在人乳腺癌中的功能影响。我们发现NBCn1在原发性乳腺癌和转移性乳腺癌中的质浆密度比匹配的正常乳腺组织高2030%。NBCn1密度的增加与Na+/H+交换体NHE1 （SLC9A1）的增加幅度相似，NHE1是一种先前与细胞迁移、增殖和恶性肿瘤有关的转运体。在原发性乳腺癌中，NBCn1的表观分子量比正常组织增加。使用ph敏感荧光团，我们发现Na+，HCO3-共转运是酸挤压的主要机制，200 μ M 4,4'-二异硫氰酸二苯乙烯-2,2'-二磺酸抑制了34 +/- 9%的人原发性乳腺癌。在细胞内pH （pHi）为bbb6.6时，依赖于CO2/HCO3的机制占总净酸挤压的>90%。Na+/H+交换活性仅在较低的ph值下显著。此外，不存在CO2/HCO3-时，稳态pHi值比存在CO2/HCO3-时低0.35 +/- 0.06个单位。综上所述，与正常乳腺组织相比，NBCn1在原发性乳腺癌和转移性乳腺癌中的表达上调。Na+，HCO3-共转运是乳腺癌中pHi的主要决定因素，适度的dids敏感性与NBCn1是主要原因一致。因此，我们的研究结果表明NBCn1的主要病理生理作用可能与临床相关。
Genome-wide association studies recently linked the locus for Na+,HCO3--cotransporter NBCn1 (SLC4A7) to breast cancer susceptibility, yet functional insights have been lacking. To determine whether NBCn1, by transporting HCO3- into cells, may dispose of acid produced during high metabolic activity, we studied the expression of NBCn1 and the functional impact of Na+,HCO3--cotransport in human breast cancer. We found that the plasmalemmal density of NBCn1 was 2030% higher in primary breast carcinomas and metastases compared to matched normal breast tissue. The increase in NBCn1 density was similar in magnitude to that observed for Na+/H+-exchanger NHE1 (SLC9A1), a transporter previously implicated in cell migration, proliferation and malignancy. In primary breast carcinomas, the apparent molecular weight for NBCn1 was increased compared to normal tissue. Using pH-sensitive fluorophores, we showed that Na+,HCO3--cotransport is the predominant mechanism of acid extrusion and is inhibited 34 +/- 9% by 200 mu M 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid in human primary breast carcinomas. At intracellular pH (pHi) levels >6.6, CO2/HCO3--dependent mechanisms accounted for >90% of total net acid extrusion. Na+/H+-exchange activity was prominent only at lower pHi-values. Furthermore, steady-state pHi was 0.35 +/- 0.06 units lower in the absence than in the presence of CO2/HCO3-. In conclusion, expression of NBCn1 is upregulated in human primary breast carcinomas and metastases compared to normal breast tissue. Na+,HCO3--cotransport is a major determinant of pHi in breast cancer and the modest DIDS-sensitivity is consistent with NBCn1 being predominantly responsible. Hence, our results suggest a major pathophysiological role for NBCn1 that may be clinically relevant.