Differential expression of osteocalcin during the metastatic progression of prostate cancer

Abstract

Abstract. Osteocalcin expression is restricted to osteoblasts and serum osteocalcin level is elevated in metastatic bone tumors including prostate tumors, which predominantly metastasizes to the bone and causes typical osteoblastic lesions. Previously, we have reported that osteocalcin RNA is widely expressed but incompletely spliced in the prostate including prostate tumors. Considering that many studies using osteocalcin-driven gene therapy have been conducted to treat hormone refractory metastatic tumors, detailed mechanisms controlling osteocalcin expression needs to be clarified. We aim to learn how osteocalcin expression is regulated during the metastatic process of prostate cancer. We applied assays of immunohistochemistry and RNA in situ hybridization in prostate tumors acquired from prostate (15) and metastatic sites, 13 from lymph node and 14 from bone. RT-PCR analysis in various cultured prostate cells was also performed. As predicted, osteocalcin RNA was highly expressed in most prostate epithelial cells of tumors, regardless of metastatic status of the tumor. However, osteocalcin protein was undetectable in tumors acquired from the primary site or lymph nodes whereas protein was highly expressed in the majority of bone-metastasized prostate tumors. RT-PCR analysis demonstrated that there was more completely spliced form of osteocalcin RNA present in bone-derived prostate cancer cells. Our data suggest that osteocalcin RNA was expressed but not completely spliced in non-bone environment, ultimately resulting in improper production of osteocalcin protein. This study explains why serum osteocalcin level is increased in patients with bone-metastasized prostate cancers. Yet, it remains to be clarified what regulates bone-specific osteocalcin RNA splicing in prostate tumors.

Osteocalcin—A Versatile Bone-Derived Hormone

“…A query in the current literature underscores the importance of an accurate regulation of osteocalcin and Gprc6a . Low levels of these two factors result in testicular insufficiency but high serum levels of osteocalcin (30–32) as well as overexpression of Gprc6a (33) have been linked to the development of prostate cancer. Furthermore, knocking out Gprc6a using CRISPR/Cas9 technology abolished osteocalcin-mediated activation of ERK, AKT, mTOR signaling and cell proliferation in human prostate cancer xenograft models (34).…”

Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis

“…Several studies showed that osteocalcin was decreased in NSCLC patients with bone metastasis [138,139]. In prostate cancer, some studies demonstrated significantly elevated osteocalcin levels in bone metastasis whereas other studies demonstrated no difference [140][141][142]. Taking into account its poor specificity, limited accuracy, and high biological variability, osteocalcin appears to be less than ideal for the diagnosis and prognosis of bone metastases.…”

Biomarkers for Prostate Cancer Bone Metastasis Detection and Prediction

“…It is synthesized by osteoblasts during osteoid production and is later released into the bloodstream to promote bone growth [51]. Studies have shown that PCa BM patients exhibit higher OC levels [30,47,52], since osteoblasts' synthesis of OC is very closely tied to the progression of PCa metastasis [52,53]. Thus, elevated serum OC levels are regarded as signs of metastatic disease for PCa.…”