Kong Xiaoyuan, Wang Xiaoqin, Xu Weidong, Behera Sumita, Hellermann Gary, Kumar Arun, Lockey Richard F, Mohapatra Subhra, Mohapatra Shyam S
Joy McCann Culverhouse Airway Disease and Nanomedicine Research Center, Allergy and Immunology Division, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Cancer Res. 2008 Jan 1;68(1):249-56. doi: 10.1158/0008-5472.CAN-07-3086.
The receptor for atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPRA), is expressed in cancer cells, and natriuretic peptides have been implicated in cancers. However, the direct role of NPRA signaling in tumorigenesis remains elusive. Here, we report that NPRA expression and signaling is important for tumor growth. NPRA-deficient mice showed significantly reduced antigen-induced pulmonary inflammation. NPRA deficiency also substantially protected C57BL/6 mice from lung, skin, and ovarian cancers. Furthermore, a nanoparticle-formulated interfering RNA for NPRA attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH(2)-terminal peptide of the ANP prohormone, which down-regulates NPRA expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. The antitumor activity of NP73-102 was in part attributed to apoptosis of tumor cells. Western blot and immunohistochemistry staining indicated that the transcription factor, nuclear factor-kappaB, was inactivated, whereas the level of tumor suppressor retinoblastoma protein was up-regulated in the lungs of NPRA-deficient mice. Furthermore, expression of vascular endothelial growth factor was down-regulated in the lungs of NPRA-deficient mice compared with that in wild-type mice. These results suggest that NPRA is involved in tumor angiogenesis and represents a new target for cancer therapy.
心房利钠肽（ANP）的受体，即利钠肽受体A（NPRA），在癌细胞中表达，并且利钠肽与癌症有关。然而，NPRA信号传导在肿瘤发生中的直接作用仍不清楚。在此，我们报告NPRA的表达和信号传导对肿瘤生长很重要。NPRA缺陷小鼠的抗原诱导的肺部炎症显著减轻。NPRA缺陷也能使C57BL/6小鼠免受肺癌、皮肤癌和卵巢癌的侵害。此外，一种纳米颗粒配方的NPRA干扰RNA可减轻小鼠的B16黑色素瘤肿瘤。编码ANP前体激素的NH(2)末端肽NP73-102的质粒的异位表达下调了NPRA的表达，也抑制了裸鼠中A549细胞的肺转移以及免疫活性BALB/c小鼠中Line 1细胞的肿瘤发生。NP73-102的抗肿瘤活性部分归因于肿瘤细胞的凋亡。蛋白质免疫印迹和免疫组织化学染色表明，转录因子核因子-κB失活，而NPRA缺陷小鼠肺中的肿瘤抑制蛋白视网膜母细胞瘤蛋白水平上调。此外，与野生型小鼠相比，NPRA缺陷小鼠肺中血管内皮生长因子的表达下调。这些结果表明，NPRA参与肿瘤血管生成，是癌症治疗的一个新靶点。
