ABSTRACT
The aim of this study was to analyze the expression, biological role and clinical relevance of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA), and LPA receptors (LPAR) in high-grade serous carcinoma (HGSC). mRNA expression by qRT-PCR of LPAR1-6 was analyzed in 155 HGSC specimens (88 effusions, 67 solid lesions). ATX mRNA expression was analyzed in 97 specimens. ATX, ERK, and AKT protein expression was studied by Western blotting. LPAR2 mRNA was overexpressed in HGSC cells in effusions compared to solid lesions, with opposite findings for LPAR3 and LPAR6 mRNA and ATX protein. Higher LPAR1 levels were significantly related to longer overall survival (OS) in pre-chemotherapy effusions (p = 0.027). Conversely, higher expression of LPAR1, LPAR2, and LPAR5 in post-chemotherapy effusions was significantly associated with shorter OS (p = 0.037, p = 0.025 and p = 0.021, respectively) and progression-free survival (PFS) (p < 0.001, p = 0.007 and p < 0.001, respectively) in univariate survival analysis. LPAR1 mRNA expression was an independent prognosticator of OS in patients with pre-chemotherapy effusions and PFS in patients with post-chemotherapy effusions (p = 0.013 both). In conclusion, LPAR mRNA and ATX protein levels are anatomic site-dependent in HGSC and the former are informative of disease outcome.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma/enzymology , Lysophospholipids/metabolism , Neoplasms, Cystic, Mucinous, and Serous/enzymology , Ovarian Neoplasms/enzymology , Phosphoric Diester Hydrolases/metabolism , Receptors, Lysophosphatidic Acid/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Carcinoma/genetics , Carcinoma/secondary , Carcinoma/therapy , Disease-Free Survival , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Multivariate Analysis , Neoplasm Grading , Neoplasm Staging , Neoplasms, Cystic, Mucinous, and Serous/genetics , Neoplasms, Cystic, Mucinous, and Serous/secondary , Neoplasms, Cystic, Mucinous, and Serous/therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , Phosphoric Diester Hydrolases/genetics , Phosphorylation , Proportional Hazards Models , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , Receptors, Lysophosphatidic Acid/genetics , Risk Factors , Signal Transduction , Time Factors , Treatment OutcomeABSTRACT
The present study analyzed the expression and clinical role of the transforming growth factor-ß (TGFß) pathway in high-grade serous carcinoma (HGSC), with focus on malignant effusions. TGFß1-3 and TGFßRI-III mRNA expression by qRT-PCR was analyzed in 70 HGSC effusions and 55 solid specimens (28 ovarian, 27 abdominal metastases). Protein expression of Smad2 and Smad3 and their phosphorylated forms by Western blotting was analyzed in 73 specimens (42 effusions, 13 ovarian carcinomas, 18 solid metastases). Expression was analyzed for association with anatomic site and clinical parameters, including survival. TGFßRI and TGFßRII mRNA was overexpressed in effusions and solid metastases, particularly the former, compared to that in the ovarian tumors (p < 0.001 to p = 0.05), with anatomic site-dependent expression of splice variants. Conversely, Smad2, p-Smad2, and p-Smad3 were overexpressed in solid specimens (ovarian and peritoneal) compared to those in effusions (p < 0.001 for all). In univariate survival analysis, higher TGFßRI variant 1 and TGFßRIII mRNA levels were associated with a trend for shorter overall survival in patients with post-chemotherapy effusions (p = 0.066 and p = 0.087, respectively), and the latter was an independent prognostic marker in Cox multivariate analysis (p = 0.041). Smad3 protein expression was associated with a trend for shorter overall survival in univariate survival analysis (p = 0.052). TGFß receptor splice variant expression is anatomic site-dependent in HGSC. Elevated levels of TGFß signaling pathway mRNAs are seen in metastatic HGSC, but are not accompanied by increased Smad expression and activation in HGSC effusions, evidence of failure to activate canonical TGFß signaling. Assessment of the prognostic role of this pathway in HGSC effusions merits further research.
