Interleukin-22 Is Frequently Expressed in Small- and Large-Cell Lung Cancer and Promotes Growth in Chemotherapy-Resistant Cancer Cells

• Published in: Journal of thoracic oncology 2013-08, Vol.8 (8), p.1032-1042
• Main Authors: Kobold, Sebastian, Völk, Stefanie, Clauditz, Till, Küpper, Natascha Jennifer, Minner, Sarah, Tufman, Amanda, Düwell, Peter, Lindner, Michael, Koch, Ina, Heidegger, Simon, Rothenfußer, Simon, Schnurr, Max, Huber, Rudolf Maria, Wilczak, Waldemar, Endres, Stefan
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Large Cell - chemistry; Carcinoma, Large Cell - drug therapy; Carcinoma, Large Cell - pathology; Cell Line, Tumor; Child; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; Interleukin-22; Interleukin-22-receptor 1; Interleukins - analysis; Interleukins - physiology; Large-cell lung cancer; Lung cancer; Lung Neoplasms - chemistry; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Middle Aged; Prognosis; Receptors, Interleukin - analysis; Small Cell Lung Carcinoma - chemistry; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - pathology; Small-cell lung cancer
• ISSN: 1556-0864; 1556-1380
• DOI: 10.1097/JTO.0b013e31829923c8

In lung cancer, interleukin-22 (IL-22) expression within primary tissue has been demonstrated, but the frequency and the functional consequence of IL-22 signaling have not been addressed. This study aims at analyzing the cellular effects of IL-22 on lung carcinoma cell lines and the prognostic impact of IL-22 tissue expression in lung cancer patients. Biological effects of IL-22 signaling were investigated in seven lung cancer cell lines by Western blot, flow cytometry, real-time polymerase chain reaction, and proliferation assays. Tumor tissue specimens of two cohorts with a total of 2300 lung cancer patients were tested for IL-22 expression by immunohistochemistry. IL-22 serum concentrations were analyzed in 103 additional patients by enzyme-linked immunosorbent assay. We found the IL-22 receptor 1 (IL-22-R1) to be expressed in six of seven lung cancer cell lines. However IL-22 signaling was functional in only four cell lines, where IL-22 induced signal transducer activator of transcription 3 phosphorylation and increased cell proliferation. Furthermore, IL-22 induced the expression of antiapoptotic B-cell lymphoma 2, but did not rescue tumor cells from carboplatin-induced apoptosis. Cisplatin-resistant cell lines showed a significant up-regulation of IL-22-R1 along with a stronger proliferative response to IL-22 stimulation. IL-22 was preferentially expressed in small- and large-cell lung carcinoma (58% and 46% of cases, respectively). However, no correlation between IL-22 expression by immunohistochemistry and prognosis was observed. IL-22 is frequently expressed in lung cancer tissue. Enhanced IL-22-R1 expression and signaling in chemotherapy-refractory cell lines are indicative of a protumorigenic function of IL-22 and may contribute to a more aggressive phenotype.