Morphoproteomics Demonstrates Activation of mTORC2 in Aggressive Histologic Variants of Papillary Thyroid Carcinoma.
Jing Liu, Robert E Brown. University of Texas Health Science Center at Houston Medical School
Background: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and, in general, has an excellent prognosis with appropriate treatment. However, a small subgroup of patients has aggressive or radioactive-iodine-resistant PTCs of which the tumorigenesis is not quite understood and the criteria for the histologic subclassification are still controversial. Morphoproteomics is a method using immunohistochemistry to identify the expression of signal transduction pathways. In this study, we use morphoproteomics to investigate the activation of mammalian target of rapamycin (mTOR) signaling pathway in PTCs.
Design: Archival paraffin-embedded, tissue of PTC was obtained from 31 patients including 15 conventional type, 9 follicular variant, 4 tall cell variant, 1 columnar cell variant, 1 diffuse sclerosing variant, and 1 cribriform variant. Immunohistochemical stains were performed for the following three phosphorylated (p) analytes: p-mTOR (Ser 2448), p-Akt (Ser 473), and p-p70S6K (Thr 389). Chromogenic signals and subcellular compartmentalization (nuclear, cytoplasmic, and plasmalemmal) were evaluated.
Results: Immunoreactivities of p-mTOR, p-Akt, and p-p70S6K were observed in all PTCs. In addition to the expression of p-mTOR in cytoplasmic and/or plasmalemmal locations, the nuclear translocation of p-mTOR with concomitant nuclear expression of p-Akt was identified in all tall cell variant, columnar cell variant, and diffuse sclerosing variant PTCs. A strong nuclear expression of p-p70S6K was present in all PTCs.
Conclusions: The expressions of p-mTOR in cytoplasmic and/or plasmalemmal locations with concomitant nuclear expression of p-p70S6K in all PTCs indicate the activation of mTOR complex 1 (mTORC1). The nuclear translocation of p-mTOR evidences the activation of mTOR complex 2 (mTORC2) per literature and is identified only in the known aggressive histologic variants including tall cell, columnar cell, and diffuse sclerosing variants of PTC in this study. These results show the constitutive activation of mTOR signaling pathway in PTCs and provide a new insight of biologic basis for the aggressive histologic variants of PTC. The expression of mTORC2 in these variants may serve as a diagnostic marker and a therapeutic target.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 39, Tuesday Afternoon