Angiogenic miRNAs, angiopoietin axis and related TIE2-expressing monocytes affect outcome in cholangiocarcinoma

Question:

Tumor angiogenesis is modulated on epigenetic and protein levels with potential implications on immune cell responses. However, the importance of related angiogenic biomarkers in cholangiocarcinoma (CCA) is unknown. We tested human samples of CCA for expression of microRNA involved in angiogenesis, angiopoietins (Angs) and monocyte subsets expressing Ang-receptor TIE2 (TEMs) with regard to their prognostic significance after liver resection.

Methods:

Expression of miR-107, miR-126, miR-128 and miR-145 was analyzed in frozen samples of intrahepatic cholangiocarcinoma (iCC; n = 43) and hilar cholangiocarcinoma (HC; n = 45), whereas Ang-1 and Ang-2 patterns, as well as TEMs, were detected in paraffin-embedded iCC (n = 88) sections. MiRNA expression and abundance of TEMs and Angs were correlated with clinicopathologic characteristics and survival.

Results:

MiR-126 was downregulated in ˜70% of all CCA samples with high relative expression being associated with smaller tumors in HC and less lymph node metastasis in iCC. High Ang-1 expression was associated with less lymphangiosis carcinomatosa and better histological grading (all ρ< 0.05). Absence of TEMs in iCC correlated with elevated CA19 – 9 levels. High relative miR-126 and low miR-128 were associated with decreased survival in iCC and HC, respectively (all p < 0.05). High miR-126 and low miR-128 and TEMs were confirmed as independent prognostic factors for recurrence-free and overall survival (all p < 0.05).

Conclusions:

Our results suggest angiogenic miRNA, Ang-1 expression profiles and TEMs responses of prognostic value in human CCA. Besides possible functional links between angiogenic miRNA expression profiles, Angs and immune cell responses by TEM, our data have clinical implications as novel diagnostic tools.