Plakophilin 1-deficient cells upregulate SPOCK1: implications for prostate cancer progression

Abstract

Plakophilin (PKP) 1 is frequently downregulated in prostate cancer and therefore may play a tumor-suppressive role. In the present study, we stably knocked down PKP1 in the non-neoplastic, prostatic BPH-1 cell line. In the PKP1-deficient cells, the expression of keratin 14 was lost, and the apoptosis rate was significantly reduced indicating that the cells acquired new biological capabilities. Moreover, we analyzed the gene expression profile of the PKP1-deficient BPH-1 cells. Among the genes that were significantly altered upon PKP1 knockdown, we noticed several extracellular matrix (ECM)-related genes and identified sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1/testican-1) as a gene of interest. SPOCK1 is a component of the ECM and belongs to a matricellular protein family named secreted protein, acidic, cysteine-rich (SPARC). The role of SPOCK1 in prostate cancer has not been clearly elucidated. We analyzed SPOCK1 mRNA expression levels in different cancer databases and characterized its expression in 136 prostatic adenocarcinomas by immunohistochemistry and western blot. SPOCK1 revealed a cytoplasmic localization in the glandular epithelium of the prostate and showed a significant upregulation of mRNA and protein in prostate tumor samples. Our findings support the hypothesis that PKP1 may have a tumor-suppressive function and suggest an important role of SPOCK1 in prostate tumor progression. Collectively, altered expression of PKP1 and SPOCK1 appears to be a frequent and critical event in prostate cancer.

Stromal SPOCK1 supports invasive pancreatic cancer growth

“…Previous publications have demonstrated a role for SPOCK1 in cancer types such as breast cancer (Fan et al, 2016), prostate cancer Yang et al, 2015), glioblastomas , urothelial carcinomas (Ma et al, 2016), ovarian cancer , esophageal squamous cell carcinomas (Song et al, 2015), gallbladder cancer (Shu et al, 2015), lung cancer (Miao et al, 2013), and hepatocellular carcinomas (Li et al, 2013). All these studies focused on the epithelial fraction.…”

SPOCK1 Is a Novel Transforming Growth Factor-β–Induced Myoepithelial Marker That Enhances Invasion and Correlates with Poor Prognosis in Breast Cancer

“…The SPARC family of proteins consists of SPARC (osteonectin), Hevin (SPARC-like protein 1), secreted modular calcium binding protein (SMOC) 1 and 2, testican-1, 2 and 3, and follistatin like protein 1 [ 18 ]. Members of the SPARC family share a follistatin-like domain and an extracellular calcium binding E-F hand motif, regulate extracellular matrix assembly and deposition, and modulate growth factor signaling pathways [ 18 , 19 ]. In the present study, we identified SPOCK1 as a novel MEC marker.…”

MicroRNA‑155‑5p inhibits the invasion and migration of prostate cancer cells by targeting SPOCK1

“…SPOCK1 expression was found to be significantly higher in prostate carcinoma compared with that in the normal prostate gland by both Oncomine data and the results of the present study. In previous studies, SPOCK1 was identified as a novel oncogene with critical effects on the PI3K/Akt and Wnt/β-catenin pathways, the Bcl-2 family and MMPs ( 12 , 13 , 22 ).…”

“…EMT plays a key role in cancer metastasis, particularly in prostate neoplasms ( 25 ). Recent studies demonstrated that SPOCK1 regulates the EMT process during cancer metastasis ( 12 , 13 , 26 ). MMP3 and MMP9 are two mesenchymal markers that promote EMT and distant metastasis ( 27 ).…”

“…Recent studies reported that SPOCK1 is abnormally expressed in various tumors and is involved in glioblastoma cell invasion, hepatocellular carcinoma progression and the regulation of epithelial-to-mesenchymal transition (EMT) in lung cancer ( 9 – 11 ). In vitro and in vivo assays revealed that SPOCK1 promotes tumor growth and metastasis in human prostate cancer via several pathways, such as via PI3K/Akt, Wnt/catenin, Bcl-2 family and matrix metalloproteinases (MMPs) ( 12 , 13 ). However, the mechanism underlying SPOCK1 overexpression remains unclear.…”