Abstract #1546: The IL-6/Jak2/Stat3 signaling pathway upregulates ER-\#946; expression in lung adenocarcinoma cells

We have demonstrated that activation of Stat3 by autocrine IL-6 plays an important role in the pathogenesis of lung adenocarcinoma. Using affimatrix oligonuleotide array experiments, we found that expression of estrogen receptor \#946; (ER-\#946;) is upregulated in Stat3-active lung adenocarcinoma cell (PC14PE6/AS2). To confirm that ER-\#946; expression is upregulated by IL6/Jak2/Stat3 pathway, we carried out the following studies. We found that the ER-\#946; but not ER-\#945; protein was expressed in the majority of lung cancer cell lines. In PC14PE6/AS2 cells the ER-\#946; protein was upregulated by IL-6 in a dose dependent manner. In a fixed dose, IL-6 upregulates ER-\#946; expression gradually in PC14PE6/AS2 and A549 cells. The ER-\#946; mRNA detected by RT-PCR was induced by IL-6. But, pretreatmet of PC14PE6/AS2 cells with actinomycin D, a transcriptional inhibitor, did not efficiently abolish IL-6-induced ER-\#946; expression. The pretreatment with cycloheximide, a protein synthesis inhibitor, however, decreased the IL-6-induced ER-\#946; expression evidently. The results indicated that IL-6 regulated ER-\#946; expression both in transcriptional and post-transcription levels. In PC14PE6/AS2 cell and its derivatives, the ER-\#946; expression was higher in cells containing constitutively activated Stat3 (S3CC) but was barely seen in cells with dominant-negative Stat3 (S3D8 and S3D9). The regulation of ER-\#946; expression by Stat3 was further confirmed by Stat3 siRNA knockdown assay. On the contrary, neither the ER-\#946; agonist-diarylpropionitrile (DPN)-induced Stat3 expression, nor the ER-\#946; siRNA suppress Stat3 expression in PC14PE6/AS2 cells. Taken together, we clearly demonstrate that the IL-6/Jak2/Stat3 pathway is implicated in the regulation of ER-\#946; expression. To determine which downstream signaling pathways of IL-6 participated in the regulation, PC14PE6/AS2 cells were treated with various kinds of inhibitors. We found that JAK2 and MEK/ERK but not PI3K/AKT pathways are relevant. High prevalence of female lung adenocarcinoma is a hallmark of lung cancer in Oriental peoples and estrogen has been recognized as a lung cancer promoter. Therefore, further studies to understanding the interaction between Stat3 and ER-\#946; and its impact on the pathogenesis of lung adenocarcinoma is warranted.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1546.