Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan.
Mod Pathol. 2016 Nov;29(11):1424-1432. doi: 10.1038/modpathol.2016.138. Epub 2016 Jul 29.
Recently, several studies have reported that dysfunctions in protein phosphatase 2A (PP2A) caused by alterations in protein phosphatase 2 regulatory subunit A, alpha (PPP2R1A) are responsible for tumorigenesis and tumor progression in several types of cancers. The impact of PPP2R1A mutations remains unknown in gastrointestinal stromal tumors (GISTs), although mutations in KIT and PDGFRA, which result in constitutive activation of the receptor tyrosine kinase pathway, are important in GIST tumorigenesis. In this study, we performed mutation analysis of PPP2R1A to examine the frequency of PPP2R1A mutations and their clinicopathological correlation in 94 GIST cases. In addition, we performed an in vitro analysis to investigate the effects of PPP2R1A mutations on cell proliferation and kinase phosphorylation in GIST cells. Seventeen GIST cases (18%) harbored mutations in PPP2R1A. All but one of these 17 cases harbored a KIT, PDGFRA, HRAS, NRAS, or KRAS mutation as the oncogenic driver mutation, and the remaining case was immunohistochemically negative for succinate dehydrogenase B (SDHB). Multivariate analysis showed that larger tumor size, higher mitotic rate, and PPP2R1A mutation are independent prognostic factors for overall survival; however, PPP2R1A mutation was not an independent prognostic factor for disease-free survival. The transduction of GIST cells with mutant PPP2R1A induced an accelerated growth rate via increased phosphorylation of Akt1/2, ERK1/2, and WNK1, a kinase associated with angiogenesis. In addition, the transduction of GIST cells with mutant PPP2R1A caused increased c-kit phosphorylation, suggesting that c-kit is also a target of PP2A, reinforcing the tumorigenic capabilities of c-kit. Furthermore, the transducing GIST cells with wild-type PP2A dephosphorylated mutant c-kit. This study provides a new insight into the biology of GISTs and their phosphatase activity, and activated PP2A could be a therapeutic target in GISTs.
最近，有几项研究报道称，蛋白磷酸酶 2A（PP2A）的功能障碍是由于蛋白磷酸酶 2 调节亚基 A，α（PPP2R1A）的改变引起的，这与几种类型癌症的肿瘤发生和肿瘤进展有关。尽管 KIT 和 PDGFRA 的突变导致受体酪氨酸激酶途径的组成性激活，在胃肠道间质瘤（GIST）的肿瘤发生中起着重要作用，但 PPP2R1A 突变在 GIST 中的影响尚不清楚。在这项研究中，我们对 PPP2R1A 进行了突变分析，以检查 94 例 GIST 病例中 PPP2R1A 突变的频率及其与临床病理的相关性。此外，我们还进行了体外分析，以研究 PPP2R1A 突变对 GIST 细胞增殖和激酶磷酸化的影响。17 例 GIST 病例（18%）存在 PPP2R1A 突变。这 17 例中除 1 例外，均存在 KIT、PDGFRA、HRAS、NRAS 或 KRAS 作为致癌驱动突变，其余病例琥珀酸脱氢酶 B（SDHB）免疫组织化学染色阴性。多因素分析显示，肿瘤较大、有丝分裂率较高和 PPP2R1A 突变是总生存率的独立预后因素；然而，PPP2R1A 突变不是无病生存率的独立预后因素。用突变 PPP2R1A 转导 GIST 细胞可通过增加 Akt1/2、ERK1/2 和 WNK1 的磷酸化来诱导更快的生长速度，WNK1 是一种与血管生成相关的激酶。此外，用突变 PPP2R1A 转导 GIST 细胞会导致 c-kit 磷酸化增加，表明 c-kit 也是 PP2A 的靶标，增强了 c-kit 的致瘤能力。此外，用野生型 PP2A 转导 GIST 细胞可使突变 c-kit 去磷酸化。这项研究为 GIST 的生物学及其磷酸酶活性提供了新的见解，激活的 PP2A 可能成为 GIST 的治疗靶点。
