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Effect of PR55α expression on clonogenicity of pancreatic cancer cells

Legends for Supplementary Figures S1-S4

Decrease of PR55α expression in pancreatic cancer cells inhibits tumor growth.

Effect of PR55α expression on mobility of pancreatic cancer cells.

The protein phosphatase 2 (PP2A) holoenzyme consists of a catalytic subunit, a scaffold subunit, and a regulatory subunit. Based on loss-of-function analysis using PP2A catalytic inhibitors or inhibition via tumor viral antigens, limited studies suggest that PP2A is a putative tumor suppressor. However, PP2A has also been shown to facilitate the activation of oncogenic signaling pathways when associated with specific regulatory subunits. In this study, we investigated the possible oncogenic role of PP2A in pancreatic cancer. We found a striking increase in the expression of PR55α (PPP2R2A), a PP2A regulatory subunit, in pancreatic cancer cells compared with normal pancreatic epithelial cells. Consistently, PR55α expression was markedly elevated in pancreatic ductal adenocarcinoma tissues compared with adjacent normal pancreatic tissues (P < 0.0001) and correlated with poor survival of pancreatic cancer patients (P < 0.0003). RNAi-mediated depletion of PR55α in pancreatic cancer cell lines resulted in diminished phosphorylation of both AKT and ERK1/2 (MAPK3/1) and decreased protein levels of β-catenin (CTNNB1). Accordingly, pancreatic cancer cells with reduced PR55α expression exhibited significantly impaired properties of transformation, including attenuated cell growth, clonogenicity, mobility, and anchorage-independent growth. Moreover, orthotopic implantation of PR55α-depleted pancreatic cancer cells into nude mice resulted in markedly reduced tumorigenicity (P < 0.001) and distant metastases. Together, these results suggest that PR55α promotes pancreatic cancer development by sustaining hyperactivity of multiple oncogenic signaling pathways, including AKT, ERK, and Wnt. These studies also provide a basis for exploring PR55α as a diagnostic or therapeutic target in pancreatic cancer. Cancer Res; 76(8); 2243–53. ©2016 AACR.

Effect of PR55α expression on BAD and β-catenin

Clinical characteristics of the PDAC specimens used for the study of PR55α expression by IHC

Description of additional details of materials and methodologies used in this study

Functional mediastinal paragangliomas (PGs) are rare, catecholamine-secreting tumours. Surgical resection is the preferred treatment, but it can be complicated by catecholamine-related symptoms, involvement of cardiac structures and/or tumour supply from major blood vessels. We report a case of a man in his 30s with a subcarinal functional PG complicated by all three factors. The PG had arterial supplies from the right coronary and bronchial arteries, with mass effect on the left atrium. Given the high risk of intraoperative bleeding, catecholamine surges and injury to right coronary artery, we attempted a minimally invasive strategy that incorporates best practices from the few published cases on functional PGs. We show that a multidisciplinary approach involving alpha/beta blockade, preoperative embolisation of tumour blood supply, robotic-assisted tumour mobilisation and, if needed, open resection with cardiopulmonary bypass can be a safe strategy in the treatment of functional mediastinal paragangliomas adherent to cardiac structures.