Gollamudi Murthy, Nethery David, Liu Jinbo, Kern Jeffrey A
Department of Internal Medicine, Pulmonary and Critical Care Division, University Hospitals of Cleveland, Case Western Reserve University, Wearn 610, 11100 Euclid Avenue, Cleveland, OH 44106, USA.
Lung Cancer. 2004 Feb;43(2):135-43. doi: 10.1016/j.lungcan.2003.08.027.
Our prior studies identified co-expression of the human epidermal growth factor-like receptors 2 (ErbB2) and 3 (ErbB3), as well as the growth factor neuregulin-1 (NRG-1) in normal lung epithelium and lung cancers. As ErbB2 and ErbB3 dimerize to produce a high affinity receptor for NRG-1, we postulated that an autocrine growth loop was present in transformed and non-transformed pulmonary epithelial cells. To test this hypothesis, we examined four cell lines derived from human non-small cell carcinomas for: (1) ErbB2 and ErbB3 expression and endogenous activation; (2) NRG-1 expression and secretion/shedding; and (3) the effect of receptor blockade on autocrine receptor activation. Our studies found that ErbB2 and ErbB3 were expressed by each of these cell lines. In addition, the NRG-1 gene was also expressed with both major isoforms of NRG-1 (NRG-1alpha and NRG-1beta) found intracellularly. Only the NRG-1alpha isoform, however, was found secreted/shed into the culture medium. The secreted/shed NRG-1alpha was capable of activating the ErbB2/ErbB3 receptor complex expressed on the breast adenocarcinoma cell line MCF-7. Basal ErbB2 phosphorylation was identified in all lung cancer cell lines and was inhibited with an antibody that blocked the NRG-1 binding site on ErbB3. Taken together, these data show that secreted NRG-1alpha can activate the ErbB2/ErbB3 heterodimer in an autocrine fashion. The identification of a NRG-1alpha/ErbB2/ErbB3 autocrine loop raises the possibility that interruption of this loop may have therapeutic potential in lung cancer.
我们之前的研究发现，人表皮生长因子样受体2（ErbB2）和3（ErbB3）以及生长因子神经调节蛋白-1（NRG-1）在正常肺上皮细胞和肺癌中共同表达。由于ErbB2和ErbB3二聚化可产生对NRG-1的高亲和力受体，我们推测在转化和未转化的肺上皮细胞中存在自分泌生长环。为了验证这一假设，我们检测了来源于人非小细胞癌的四种细胞系，以观察：（1）ErbB2和ErbB3的表达及内源性激活；（2）NRG-1的表达及分泌/脱落；（3）受体阻断对自分泌受体激活的影响。我们的研究发现，这些细胞系均表达ErbB2和ErbB3。此外，NRG-1基因也有表达，且在细胞内发现了NRG-1的两种主要异构体（NRG-1α和NRG-1β）。然而，仅发现NRG-1α异构体分泌/脱落在培养基中。分泌/脱落的NRG-1α能够激活乳腺癌细胞系MCF-7上表达的ErbB2/ErbB3受体复合物。在所有肺癌细胞系中均检测到基础ErbB2磷酸化，且用阻断ErbB3上NRG-1结合位点的抗体可抑制这种磷酸化。综上所述，这些数据表明分泌的NRG-1α能够以自分泌方式激活ErbB2/ErbB3异二聚体。NRG-1α/ErbB2/ErbB3自分泌环的发现增加了中断该环可能对肺癌具有治疗潜力的可能性。
