Ryota Matsuoka

Cyclophilin A expression and its prognostic significance in lung adenocarcinoma: CypA expression in lung adenocarcinoma

Cyclophilin A (CypA) has been reported to be upregulated in malignant tumors. CypA expression is thought to be associated with acquisition of tumor growth and anti‐apoptotic function. Although upregulation of CypA has been reported in lung adenocarcinoma, its clinicopathological significance and roles in malignant progression remain unclear. Here we investigated the implications of CypA expression for outcome in patients with lung adenocarcinoma. Lung adenocarcinoma specimens from 198 cases were selected and reclassified according to the World Health Organization classification (4th edition) and the Noguchi classification. CypA expression was assessed by immunohistochemistry, and the H‐score was calculated on the basis of intensity and proportion. The specificity of the antibody used was confirmed by Western blotting and the cut‐off point was determined from the ROC curve. Sixty‐seven cases (33.8%) had low CypA expression (CypA‐L group) and 131 (66.2%) had high CypA expression (CypA‐H group). Many cases of adenocarcinoma in situ were CypA‐L, and advanced adenocarcinomas tended to be classified as CypA‐H. Clinically, patients with CypA‐H tumors showed a significantly poorer prognosis than those with CypA‐L tumors. This is the first investigation of the implications of the CypA expression level in terms of the clinical characteristics of resected lung adenocarcinomas.

High expression of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) is associated with poor prognosis in lung adenocarcinoma: OCIAD2 is prognostic marker of lung ad.

The clinicopathological implications of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) in lung adenocarcinoma were investigated. The expression of OCIAD2 in 191 surgically resected lung adenocarcinomas was examined using immunohistochemistry. OCIAD2 expression was quantified using the H‐score and dichotomized as high or low. High OCIAD2 protein expression was significantly correlated with vascular invasion (P = 0.0018), lymphatic permeation (P = 0.049), T factor (P = 0.0024), and pathological stage (P = 0.0003). High OCIAD2 expression was significantly associated with poorer overall survival (OS) (n = 191, P = 0.0325). In peripheral‐type lung adenocarcinomas (n = 161), high OCIAD2 expression was significantly associated with both poorer OS (P = 0.0214) and poorer disease‐free survival (P = 0.0496). Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) showed weaker OCIAD2 expression than invasive adenocarcinoma. Among small adenocarcinomas measuring 2 cm or less in greatest dimension classified according to the Noguchis classification (n = 79), invasive adenocarcinomas showed significantly higher OCIAD2 expression than non‐invasive adenocarcinomas (P = 0.0007). Interestingly, OCIAD2 was expressed heterogeneously even within a tumor, and its expression was higher in areas of invasion than in areas of in situ spread. Our results suggest that OCIAD2 could be a useful prognostic biomarker of lung adenocarcinoma.

Stratifin regulates stabilization of receptor tyrosine kinases via interaction with ubiquitin-specific protease 8 in lung adenocarcinoma

Previously we have reported that stratifin (SFN, 14-3-3 sigma) acts as a novel oncogene, accelerating the tumor initiation and progression of lung adenocarcinoma. Here, pull-down assay and LC-MS/MS analysis revealed that ubiquitin-specific protease 8 (USP8) specifically bound to SFN in lung adenocarcinoma cells. Both USP8 and SFN showed higher expression in human lung adenocarcinoma than in normal lung tissue, and USP8 expression was significantly correlated with SFN expression. Expression of SFN, but not of USP8, was associated with histological subtype, pathological stage, and poor prognosis. USP8 stabilizes receptor tyrosine kinases (RTKs) such as EGFR and MET by deubiquitination, contributing to the proliferative activity of many human cancers including non-small cell lung cancer. In vitro, USP8 binds to SFN and they co-localize at the early endosomes in lung adenocarcinoma cells. Moreover, USP8 or SFN knockdown leads to downregulation of tumor cellular proliferation and upregulation of apoptosis, p-EGFR or p-MET, which are related to the degradation pathway, and accumulation of ubiquitinated RTKs, leading to lysosomal degradation. Additionally, mutant USP8, which is unable to bind to SFN, reduces the expression of RTKs and p-STAT3. We also found that interaction with SFN is critical for USP8 to exert its autodeubiquitination function and avoid dephosphorylation by PP1. Our findings demonstrate that SFN enhances RTK stabilization through abnormal USP8 regulation in lung adenocarcinoma, suggesting that SFN could be a more suitable therapeutic target for lung adenocarcinoma than USP8.

Heterotopic production of ceruloplasmin by lung adenocarcinoma is significantly correlated with prognosis

OBJECTIVES Ceruloplasmin (CP) is a well-known copper binding protein synthesized mainly in the liver, but its expression is known to be elevated in the serum of cancer patients and in malignant tumor cells. Lung cancer is the leading cause of cancer-related death worldwide, and adenocarcinoma is the main histological type of lung cancer. However, the role of CP in lung adenocarcinoma is still unclear. Here we examined and compared the expression of CP in various histological subtypes of lung adenocarcinoma and its correlation with clinicopathological parameters. MATERIALS AND METHODS We examined CP expression in lung adenocarcinoma samples and cell lines using quantitative real-time RT-PCR and Western blot analysis. Immunohistochemistry for CP was carried out using 196 specimens of lung adenocarcinoma. RESULTS CP expression was significantly higher in invasive adenocarcinoma than in adenocarcinoma in situ (AIS), and was significantly correlated with poorer outcome, pathological stage, pT, and pN. Multivariate analysis showed that CP expression was an independent prognostic factor for lung adenocarcinoma patients. Furthermore, Western blot analysis using protein extracted from lung adenocarcinoma cell lines revealed the secreted form of CP. CONCLUSION CP is produced heterotopically in lung adenocarcinoma cells and its expression is associated with tumor progression. In view of the presence of the secreted form of CP in tumor cells, CP may be a useful biomarker for lung adenocarcinoma.

Functional Supramolecular Architectures of Dipyrrin Complexes

Dynamic formation of self-assemblies from molecular components is a useful and efficient way to produce molecular and supramolecular architectures with sophisticated functions. The labile coordination bond and dynamic covalent bond as a reversible bond have often been used to create a well-organized supramolecular self-assembly. In order to realize sophisticated novel functions of the supramolecular self-assemblies, dipyrrin complexes have recently been employed as a functional unit and incorporated into the supramolecular architectures because of their outstanding properties and functions such as a high photostability and strong light absorption/emission. This review article summarizes recent development in functional supramolecular architectures of the dipyrrin complexes produced by coordination to a metal ion and dynamic covalent bond formation. We first describe the synthesis and unique functions of a series of discrete supramolecular architectures: helicates, macrocycles, and cages. The polymeric supramolecular self-assemblies with 1D, 2D, and 3D structures are then introduced as a functional infinite supramolecular architecture.

Genetic evidence implies that the primary and relapsed tumors arise from common precursor cells in primary CNS lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra‐CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precursor cells (CPC) for primary intra‐ and relapsed extra‐CNS tumors, and further assessing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra‐ and relapsed extra‐CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra‐ and extra‐CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra‐CNS tumors and in four out of five extra‐CNS tumors. Remarkably, IgH clones in the intra‐ and the extra‐CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonal IgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor‐free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutations were detected by a droplet digital PCR method in nine out of 23 bone marrow mononuclear cells. These results suggest that intra‐ and extra‐tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rearrangement. The initiating MYD88 mutations may occur during B‐cell differentiation in BM.

Papillotubular carcinoma with an invasive micropapillary carcinoma component of the breast, characterized by a rapid increase in size due to intra-tumoral hemorrhage: A case report

Highlights • Rapidly enlarging breast tumors due to hemorrhage are clinically rare.• Invasive micropapillary carcinoma (IMPC) of breast is known to have aggressive behavior and poor clinical course compared to invasive ductal carcinoma.• Surgeons should recognize the morphology of IMPC due to its aggressive clinical behaviors.