Mouse Anti Rat osteopontin Hybridoma [NQJJJC21(2)]

Resistance to androgen deprivation therapy (ADT) is the main challenge for advanced fatal prostate cancer (PCa), which can gradually develop into metastatic castration-resistant prostate cancer (mCRPC). However, the pathologic mechanisms of mCRPC are still far from clear. Given the high incidence and mortality related to mCRPC, understanding the causes and pathogenesis of this condition as well as identifying potential biomarkers are of great importance. In the research reported here, we integrated several gene expression profiles from hormone sensitive prostate cancer (HSPC) and mCRPC datasets to identify differentially expressed genes (DEGs), key biological pathways, and cellular components. We found that extracellular matrix (ECM) genes were significantly enriched, and further filtered them using Pearson correlation analysis and stepwise regression to find ECM signatures to differentiate between the HSPC and mCRPC phenotypes. Six ECM signatures were input into K-nearest neighbor, logistic regression, naive Bayes, and random forest classifiers models. Random forest algorithm with the six-gene prognostic signatures showed best performance, which had high sensitivity and specificity for HSPC and mCRPC classification and further the six ECM signatures were validated in organoid models. Among the six ECM genes, SPP1 was identified as the key hub signature for PCa metastasis and drug resistance development; we found that both protein and mRNA expression levels of SPP1 were remarkably up-regulated in mCRPC compared with HSPC in organoid models and could regulate the androgen receptor signaling pathway. Therefore, SPP1 is a potential novel biomarker and therapeutic target for mCRPC. Further understanding of the role of SPP1 in mCRPC development may help to explore effectively therapeutic approaches for the prevention and intervention of drug resistance and metastasis.

The matricellular glycoprotein products of the SPP1 and SPARC genes play critical roles in many aggressive tumor phenotypes including gastric cancer. We sought to test whether the polymorphisms of these two genes, individually or jointly, influence gastric cancer susceptibility. Nine potentially functional, tagging single nucleotide polymorphisms (tagSNPs) of SPP1 and SPARC were selected and detected using the Kompetitive Allele Specific PCR method in 301 gastric cancer cases and 1441 healthy control subjects. We found that the genotype frequencies of SPP1 rs4754 in gastric cancer were significantly different from those in controls. The rs4754 TT genotype conferred an increased risk of gastric cancer, with unadjusted and adjusted ORs ranging from 1.75 to 1.95 (all P < 0.05). The assessment of the effect modifications of sex and age on the genetic effects also confirmed the statistically significant association of the rs4754 TT genotype with increased gastric cancer risk. Epistatic interactions were found between SPP1 rs4754 and SPARC rs1054204, rs3210714 and rs3549 (all P values for interaction < 0.05). During the assessment of the epistatic effects between pairs of interacting factors, increased gastric cancer risk was observed in the combined presence of the SPP1 rs4754 TT genotype and the common genotypes of interacting SPARC SNPs, with ORs ranging from 3.94 to 4.41. When the genetic influence of SPP1 rs4754 TT was excluded, the genetic effects of the SPARC rs1054204, rs3210714 and rs3549 common genotypes on gastric cancer susceptibility switched from being risky to beneficial. These data reveal an association between the SPP1 rs4754 polymorphism and altered risk of gastric cancer and highlight an important role of the epistatic effects of SPP rs4754 with SPARC polymorphisms in gastric carcinogenesis. Additional functional experiments and independent large-scale studies, especially in other ethnic populations, are needed to confirm our results.