TY - JOUR
T1 - IL8 expression is associated with prostate cancer aggressiveness and androgen receptor loss in primary and metastatic prostate cancer
AU - Maynard, Janielle P.
AU - Ertunc, Onur
AU - Kulac, Ibrahim
AU - Baena-Del Valle, Javier A.
AU - DeMarzo, Angelo M.
AU - Sfanos, Karen S.
N1 - Funding Information:
This work was supportedby Departmentof Defense PCRP awards W81XWH-14-1-0364 and W81XWH-17-1-0286 (to K.S. Sfanos), Department of Defense PCRP award W81XWH-17-1-0292 (to J.P. Maynard), and Department of Defense PCRP awards W81XWH-18-2-0013, W81XWH-18-2-0015, and W81XWH-18-2-0017 PCBN (to K.S. Sfanos and A.M. De Marzo). The authors thank the patients and their families who participated in the studies at Johns Hopkins. We would like to thank and acknowledge Dr. Jody Hooper and the Legacy Gift Rapid Autopsy Program at Johns Hopkins for assistance with autopsy specimens. We thank Dr. Eva Corey and Dr. Colm Morrissey for providing the LuCaP TMAs. We also thank Dr. Paula Hurley and Dr. Michael Haffner for helpful discussions and Jessica Hicks for help with IHC.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020
Y1 - 2020
N2 - Chronic inflammation and African ancestry are implicated in prostate cancer aggressiveness, and inflammation-related genes are more highly expressed in prostate cancer in African American men. IL8 secretion is also implicated in prostate cancer progression and castration resistance. We used RNA in situ hybridization to localize IL1b, IL6, IL8, and IL10 mRNA in low- and high-grade prostate cancer from African American and European American men. IL8 was the most abundantly expressed and the only interleukin detected in tumor cells. We further interrogated IL8 expression in primary and metastatic prostate cancer tissue microarrays and both androgen-dependent and castration-resistant patient-derived xenografts (PDX). IL8 was significantly increased in both tumor and benign regions of higher grade cases (ISUP Grade Group 4-5), but there was no difference between races. We determined that IL8 expression in prostate cancer cell lines, distant metastases, and PDX lines was associated with androgen receptor (AR) loss, but not castration resistance. Reciprocal IL8 and AR expression was also observed in high IL8-expressing atrophy lesions with simultaneous AR downregulation. Finally, we show that IL8 is likely repressed by AR binding to the IL8 promoter and is inducible in prostate cancer cells stimulated with lipopolysaccharide only in cells with AR loss. Likewise, AR knockdown in androgen-dependent cells induced IL8 expression, further demonstrating thatAR represses IL8 expression. In conclusion, IL8 expression in the tumor microenvironment is associated with aggressive prostate cancer and with AR loss in metastatic disease.
AB - Chronic inflammation and African ancestry are implicated in prostate cancer aggressiveness, and inflammation-related genes are more highly expressed in prostate cancer in African American men. IL8 secretion is also implicated in prostate cancer progression and castration resistance. We used RNA in situ hybridization to localize IL1b, IL6, IL8, and IL10 mRNA in low- and high-grade prostate cancer from African American and European American men. IL8 was the most abundantly expressed and the only interleukin detected in tumor cells. We further interrogated IL8 expression in primary and metastatic prostate cancer tissue microarrays and both androgen-dependent and castration-resistant patient-derived xenografts (PDX). IL8 was significantly increased in both tumor and benign regions of higher grade cases (ISUP Grade Group 4-5), but there was no difference between races. We determined that IL8 expression in prostate cancer cell lines, distant metastases, and PDX lines was associated with androgen receptor (AR) loss, but not castration resistance. Reciprocal IL8 and AR expression was also observed in high IL8-expressing atrophy lesions with simultaneous AR downregulation. Finally, we show that IL8 is likely repressed by AR binding to the IL8 promoter and is inducible in prostate cancer cells stimulated with lipopolysaccharide only in cells with AR loss. Likewise, AR knockdown in androgen-dependent cells induced IL8 expression, further demonstrating thatAR represses IL8 expression. In conclusion, IL8 expression in the tumor microenvironment is associated with aggressive prostate cancer and with AR loss in metastatic disease.
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U2 - 10.1158/1541-7786.MCR-19-0595
DO - 10.1158/1541-7786.MCR-19-0595
M3 - Article
C2 - 31604846
AN - SCOPUS:85077475361
SN - 1541-7786
VL - 18
SP - 153
EP - 165
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 1
ER -