title: Loss of p53 attenuates the contribution of IL-6 deletion on suppressed tumor progression and extended survival in Kras-driven murine lung cancer.
abstract: Interleukin-6 (IL-6) is involved in lung cancer tumorigenesis, tumor progression, metastasis, and drug resistance. Previous studies show that blockade of IL-6 signaling can inhibit tumor growth and increase drug sensitivity in mouse models. Clinical trials in non-small cell lung cancer (NSCLC) reveal that IL-6 targeted therapy relieves NSCLC-related anemia and cachexia, although other clinical effects require further study. We crossed IL-6(-/-) mice with Kras(G12D) mutant mice, which develop lung tumors after activation of mutant Kras(G12D), to investigate whether IL-6 inhibition contributes to tumor progression and survival time in vivo. Kras(G12D); IL-6(-/-) mice exhibited increased tumorigenesis, but slower tumor growth and longer survival, than Kras(G12D) mice. Further, in order to investigate whether IL-6 deletion contributes to suppression of lung cancer metastasis, we generated Kras(G12D); p53(flox/flox); IL-6(-/-) mice, which developed lung cancer with a trend for reduced metastases and longer survival than Kras(G12D); p53(flox/flox) mice. Tumors from Kras(G12D); IL-6(-/-) mice showed increased expression of TNFα and decreased expression of CCL-19, CCL-20 and phosphorylated STAT3(pSTAT3) than Kras(G12D) mice; however, these changes were not present between tumors from Kras(G12D); p53(flox/flox); IL-6(-/-) and Kras(G12D); p53(flox/flox) mice. Upregulation of pSTAT3 and phosphorylated AKT(pAKT) were observed in Kras(G12D) tumors with p53 deletion. Taken together, these results indicate that IL-6 deletion accelerates tumorigenesis but delays tumor progression and prolongs survival time in a Kras-driven mouse model of lung cancer. However, these effects can be attenuated by p53 deletion.
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, China ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America ; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Tan
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Jishuai
authors.initials: J
authors.lastname: Zhang
authors.forename: Yanxiao
authors.initials: Y
authors.lastname: Wang
authors.forename: Jicheng
authors.initials: J
authors.lastname: Chen
authors.forename: Xiubin
authors.initials: X
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Ye
authors.forename: Chuanhao
authors.initials: C
authors.lastname: Tang
authors.forename: Xuan
authors.initials: X
authors.lastname: Cheng
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D054415:Chemokine CCL19 / Q000235:genetics / Q000378:metabolism; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
chemical_list: C493447:CCL20 protein, mouse; C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D054418:Chemokine CCL20; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)