{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:55:57Z","timestamp":1778658957675,"version":"3.51.4"},"reference-count":57,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,1,5]],"date-time":"2015-01-05T00:00:00Z","timestamp":1420416000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Tissue inhibitor of metalloproteinase\u20101 (TIMP\u20101) is a 28.5\u2009kDa secreted glycoprotein that inhibits matrix metalloproteinase (MMP) activity. Our group has previously shown that elevated plasma TIMP\u20101 levels predict poor survival in metastatic castration\u2010resistant prostate cancer (CRPC) patients; however, the underlying source and impact of elevated circulating TIMP\u20101 protein is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>In this study, we used qRT\u2010PCR, ELISA and immunohistochemistry to evaluate TIMP\u20101 expression in androgen\u2010sensitive and resistant prostate cancer (PC) cell lines, tumor tissues and patient sera, and to correlate TIMP\u20101 levels to expression of chromogranin A (CGA), an established marker of neuroendocrine differentiation (NED). We also explored the relationship between TIMP\u20101 overexpression and induction of NED by overexpressing TIMP\u20101 in androgen\u2010sensitive LNCaP cells, as well as by inducing NED of LNCaP cells with IL\u20106.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Patients with CRPC have significantly higher serum TIMP\u20101 levels compared to patients with hormone\u2010sensitive disease. Although circulating TIMP\u20101 levels were increased, peripheral blood cells were not the source of elevation. Instead, elevated TIMP\u20101 expression was associated with higher expression of CGA in both blood and metastatic tumor tissue. We further show that androgen receptor (AR) and PSA non\u2010expressing prostate cancer cell lines known to display NED phenotypes such as PC\u20103, PC\u20103M, and DU145 cells, expressed high levels of TIMP\u20101, in contrast to AR (+) and PSA (+) adenocarcinoma cell lines such as LNCaP, VCaP, and LAPC\u20104, which had barely detectable levels of TIMP\u20101. In addition, ectopic overexpression of TIMP\u20101 in LNCaP cells did not induce NED. However, TIMP\u20101 mRNA expression was elevated &gt;10\u2010fold during IL\u20106\u2010induced NED of LNCaP cells, suggesting that TIMP\u20101 overexpression accompanies, but is not the driving force for NED. Finally, we show that conditioned media from androgen\u2010resistant PC\u20103, PC\u20103M, and DU145 cells induced TIMP\u20101 mRNA expression in primary prostate stromal fibroblasts in an ERK and NF\u2010\u03baB dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>We provide in vitro and clinical evidence to support the association between NED and elevated circulating TIMP\u20101 expression in CRPC. Our observation supports further evaluation of TIMP\u20101 as a tissue and serum biomarker for NED in CRPC. <jats:italic>Prostate 75: 616\u2013627, 2015<\/jats:italic>. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.22945","type":"journal-article","created":{"date-parts":[[2015,1,5]],"date-time":"2015-01-05T21:50:47Z","timestamp":1420494647000},"page":"616-627","source":"Crossref","is-referenced-by-count":19,"title":["Elevated circulating tissue inhibitor of metalloproteinase 1 (TIMP\u20101) levels are associated with neuroendocrine differentiation in castration resistant prostate cancer"],"prefix":"10.1002","volume":"75","author":[{"given":"Yixuan","family":"Gong","sequence":"first","affiliation":[{"name":"Division of Hematology and Medical Oncology The Tisch Cancer Institute Mount Sinai School of Medicine New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uma 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