Mariko Tsukagoshi

Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma

Patients with extrahepatic cholangiocarcinoma (EHCC) have a poor prognosis; postoperative survival depends on cancer progression and therapeutic resistance. The mechanism of EHCC progression needs to be clarified to identify ways to improve disease prognosis. Stathmin1 (STMN1) is a major cytosolic phosphoprotein that regulates microtubule dynamics and is associated with malignant phenotypes and chemoresistance in various cancers. Recently, STMN1 was reported to interact with p27, an inhibitor of cyclin‐dependent kinase complexes. Eighty EHCC cases were studied using immunohistochemistry and clinical pathology to determine the correlation between STMN1 and p27 expression; RNA interference to analyze the function of STMN1 in an EHCC cell line was also used. Cytoplasmic STMN1 expression correlated with venous invasion (P = 0.0021) and nuclear p27 underexpression (P = 0.0011). Patients in the high‐STMN1‐expression group were associated with shorter recurrence‐free survival and overall survival than those in the low‐expression group. An in vitro protein‐binding assay revealed that cytoplasmic STMN1 bound to p27 in the cytoplasm, but not in the nucleus of EHCC cells. Moreover, p27 accumulated in EHCC cells after STMN1 suppression. STMN1 knockdown inhibited proliferation and increased the sensitivity of EHCC cells to paclitaxel. STMN1 contributes to a poor prognosis and cancer progression in EHCC patients. Understanding the regulation of p27 by STMN1 could provide new insights for overcoming therapeutic resistance in EHCC.

Xanthogranulomatous cholecystitis: Difficulty in differentiating from gallbladder cancer.

AIM To compare cases of xanthogranulomatous cholecystitis (XGC) and advanced gallbladder cancer and discuss the differential diagnoses and surgical options. METHODS From April 2000 to December 2013, 6 XGC patients received extended surgical resections. During the same period, 16 patients were proven to have gallbladder (GB) cancer, according to extended surgical resection. Subjects chosen for analysis in this study were restricted to cases of XGC with indistinct borders with the liver as it is often difficult to distinguish these patients from those with advanced GB cancer. We compared the clinical features and computed tomography findings between XGC and advanced GB cancer. The following clinical features were retrospectively assessed: age, gender, symptoms, and tumor markers. As albumin and the neutrophil/lymphocyte ratio (NLR) are prognostic in several cancers, we compared serum albumin levels and the NLR between the two groups. The computerized tomography findings were used to compare the two diseases, determine the coexistence of gallstones, the pattern of GB thickening (focal or diffuse), the presence of a hypoattenuated intramural nodule, and continuity of the mucosal line. RESULTS Based on the preoperative image findings, we suspected GB carcinoma in all cases including XGC in this series. In addition, by pathological examination, we found that the group of patients with XGC developed inflammatory disease after surgery. Patients with XGC tended to have abdominal pain (4/6, 67%). However, there was no significant difference in clinical symptoms, including fever, between the two groups. Serum albumin and NLR were also similar in the two groups. Serum tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), tended to increase in patients with GB cancer. However, no significant differences in tumor markers were identified. On the other hand, gallstones were more frequently observed in patients with XGC (5/6, 83%) than in patients with GB cancer (4/16, 33%) (P = 0.0116). A hypoattenuated intramural nodule was found in 3 patients with XGC (3/6, 50%), but in only 1 patient with GB cancer (1/16, 6%) (P = 0.0024). The GB thickness, continuous mucosal line, and bile duct dilatation showed no significant differences between XGC and GB cancer. CONCLUSION Although XGC is often difficult to differentiate from GB carcinoma, it is possible to obtain an accurate diagnosis by careful intraoperative gross observation, and several intraoperative frozen sections.

Overexpression of natural killer group 2 member D ligands predicts favorable prognosis in cholangiocarcinoma.

The natural killer group 2 member D (NKG2D) receptor and its ligands are important mediators of immune responses to tumors. NKG2D ligands are overexpressed in several malignant tumor types; however, the prognostic value of these ligands is unclear. Here, we aimed to elucidate the role of NKG2D ligands in extrahepatic cholangiocarcinoma (EHCC). We therefore investigated the expression of the NKG2D receptor and its ligands MHC class I chain‐related proteins A and B (MICA/B), unique long 16 binding protein (ULBP) 1, and ULBP2/5/6 in resected specimens from 82 patients with EHCC. All NKG2D ligands were highly expressed in EHCC. High expression of MICA/B or ULBP2/5/6 correlated with overall and disease‐free survival. In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease‐free survival. Concurrent high expression of multiple NKG2D ligands revealed significantly better overall and disease‐free survival than that observed with the overexpression of any one NKG2D ligand. Co‐expression of multiple NKG2D ligands was an independent prognostic indicator of improved survival. Furthermore, co‐overexpression of multiple NKG2D ligands was significantly correlated with high expression of the NKG2D receptor. Inhibiting interactions between multiple NKG2D ligands and the NKG2D receptor might be a promising approach for controlling cancer progression and improving patient prognosis in EHCC.

Association of RAB5 overexpression in pancreatic cancer with cancer progression and poor prognosis via E-cadherin suppression

Pancreatic cancer is a common type of cancer with poor prognosis worldwide. Postoperative survival depends on the existence of metastasis. Elucidation of the mechanism underlying cancer progression is important to improve prognosis. The RAS-associated protein RAB5 activates intracellular membrane trafficking, and RAB5 expression is correlated to progression and epithelial mesenchymal transition in various cancers. The expression of RAB5 and E-cadherin in 111 pancreatic cancer samples was investigated by immunohistochemical staining, and the relationship among RAB5 expression, clinicopathological factors, and E-cadherin expression was assessed. Furthermore, RAB5 suppression analysis by siRNA was performed to determine the roles of RAB5 in morphological change, proliferation potency, cell migration ability, and invasiveness of the pancreatic cancer cell line. High RAB5 expression correlated with the presence of lymphatic invasion and venous invasion and low E-cadherin expression. Patients with high RAB5 expression had a poorer prognosis than those with low RAB5 expression. RAB5 suppression in pancreatic cancer cells enhanced E-cadherin expression; changed cell morphology from spindle to round; and inhibited proliferation, invasion, and cell migration. RAB5 contributes to poor prognosis and progression in pancreatic cancer patients. It may be a promising candidate for individualized therapy in refractory pancreatic cancer.

Relationship between 18-F-fluoro-deoxy-d-glucose uptake and expression of glucose transporter 1 and pyruvate kinase M2 in intrahepatic cholangiocarcinoma

BACKGROUND Cholangiocellular carcinoma is characterized by elevated glucose consumption, resulting in an increased uptake of 18F-2-fluoro-2-deoxy-d-glucose (18F-FDG). This study investigates the relationship between 18F-FDG uptake and tumour glucose metabolism. METHODS This was a retrospective analysis of 19 patients with cholangiocellular carcinoma. Immunohistochemistry for glucose transporter 1 and pyruvate kinase type M2 were performed. Overall tumour glucose metabolism was evaluated by measuring 18F-FDG uptake and the protein expression levels of glucose transporter 1 and pyruvate kinase type M2. RESULTS 18F-FDG uptake had a strong positive correlation with histological differentiation. Both tumour status (p=0.044) and tumour size (p=0.011) were correlated with primary tumour 18F-FDG uptake. Glucose transporter 1 expression correlated with histological differentiation (p=0.017), while pyruvate kinase type M2 expression tended to correlate with lymph node metastasis (p=0.051). Glucose transporter 1 expression was strongly related to the standard uptake value (p=0.001), but that of pyruvate kinase type M2 was not (p=0.461). CONCLUSIONS Glucose transporter 1 expression exhibits a strong correlation with 18F-FDG uptake in cholangiocellular carcinoma tissue, while pyruvate kinase type M2 expression was not associated with fluoro-2-deoxy-d-glucose uptake. In addition to its glycolytic function, pyruvate kinase type M2 has a variety of roles and its expression may enhance tumour cell invasion and promote the lymph node metastasis of intrahepatic cholangiocarcinoma.

High expression of karyopherin‐α2 and stathmin 1 is associated with proliferation potency and transformation in the bile duct and gall bladder epithelia in the cases of pancreaticobiliary maljunction

Pancreaticobiliary maljunction (PBM) may be associated with an increased frequency of gall bladder cancer with no bile duct dilation. Karyopherin‐α2 (KPNA2) and stathmin 1 (STMN1) were reported to play important roles in carcinogenesis and cancer progression.

Giant Cholangiolocellular Carcinoma With Early Recurrence That Was Difficult to Distinguish From Cholangiocellular Carcinoma: Report of a Case

Cholangiolocellular carcinoma (CoCC) is a rare type of malignant liver tumor derived from hepatic stem cells, which exist in the canals of Hering. However, the characteristics of CoCC have not been clarified. In general, CoCC is associated with a better prognosis than cholangiocellular carcinoma (CCC). Here, we report a case of giant CoCC, which was difficult to distinguish from CCC and showed early recurrence and necrosis inside the tumor. A 59-year-old man was diagnosed with CCC based on preoperative imaging. The diameter of the tumor was approximately 14 cm, and he subsequently underwent extended right lobectomy of the liver. Histopathologic analysis revealed that tumor cells proliferated and replaced the surrounding normal liver cell cords in front of the tumor. Furthermore, the tumor cells were positive for cytokeratin 19 and epithelial membrane antigen. Epithelial membrane antigen staining pattern was positive on the membranous area of the lumen. Therefore, the tumor was diagnosed as CoCC. Although adjuvant chemotherapy was performed, intrahepatic recurrence occurred at 4 months after surgery. We present here the novel characteristics of CoCC that show early recurrence and necrosis within the tumor. These characteristics have not previously been reported in patients with CoCC.

Overexpression of karyopherin-α2 in cholangiocarcinoma correlates with poor prognosis and gemcitabine sensitivity via nuclear translocation of DNA repair proteins

Cholangiocarcinoma is a highly malignant tumor, and the development of new therapeutic strategies is critical. Karyopherin-α2 (KPNA2) functions as an adaptor that mediates nucleocytoplasmic transport. Specifically, KPNA2 transports one of the important DNA repair machineries, the MRE11-RAD50-NBS1 (MRN) complex, to the nucleus. In this study, we clarified the significance of KPNA2 in cholangiocarcinoma. KPNA2 expression evaluated by immunohistochemical analysis was common in malignant tissue but rare in adjacent noncancerous tissues. KPNA2 overexpression was significantly correlated with poor prognosis and was an independent prognostic factor after surgery. In patients with cholangiocarcinoma who received gemcitabine after surgery, KPNA2 overexpression tended to be a prognostic indicator of poor overall survival. In KPNA2-depleted cholangiocarcinoma cells, proliferation was significantly decreased and gemcitabine sensitivity was enhanced in vitro and in vivo. Expression of KPNA2 and the MRN complex displayed colocalization in the nucleus. In addition, nuclear localization of the MRN complex was regulated by KPNA2 in vitro. These results suggest that KPNA2 expression may be a useful prognostic and predictive marker of gemcitabine sensitivity and survival. The regulation of KPNA2 expression may be a new therapeutic strategy for cholangiocarcinoma.

Perioperative management of hepatectomy in patients with interstitial pneumonia: a report of three cases and a literature review

PurposeInterstitial pneumonia (IP) is a progressive and irreversible fibrosis and can be fatal if acute exacerbation (AE) occurs. While a useful risk-scoring system has been established for lung surgery, no risk evaluation exists for AE of IP related to non-pulmonary surgery. The objective of this review is to describe the management for patients with IP.MethodsWe experienced three hepatectomy cases with IP. The first was a 72-year-old male patient diagnosed with hepatocellular carcinoma. Preoperative computed tomography (CT) revealed IP with reticular shadow at the base of both lungs. After hepatectomy, his IP became acutely exacerbated and did not improve with steroid or sivelestat treatment. The second was a 74-year-old male patient diagnosed with hepatocellular carcinoma, and the third was a 75-year-old male patient with liver metastasis. In both these cases, CT revealed a reticular shadow in the lung fields, with increased serum KL-6 levels. We administered pirfenidone for perioperative management, during which time no respiratory complications occurred.ResultsPerioperative management with pirfenidone for hepatectomy accompanied by IP was successful in our cases.ConclusionWe reviewed reports on the perioperative prevention, intraoperative risk factors, and treatment of postoperative AE of IP and summarized the perioperative management techniques for IP patients undergoing non-pulmonary surgery.

Enhanced karyopherin-α2 expression is associated with carcinogenesis in patients with intraductal papillary mucinous neoplasms

BACKGROUND/OBJECTIVES Intraductal papillary mucinous neoplasms (IPMN) can become malignant. Karyopherin-α2 (KPNA2) plays a central role in nucleocytoplasmic transport and is associated with various types of cancer. The current study examined pancreatic KPNA2 expression in cancer patients and evaluated its association with clinicopathological factors, cancer cell proliferation. METHODS KPNA2 expression was investigated by immunohistochemistry in 40 surgically resected IPMN samples and its association with clinicopathological factors and Ki-67 expression were examined. RESULTS Eighteen IPMN samples (45% of patients) showed positive KPNA2 expression. KPNA2 expression levels in IPMN tissue with invasive carcinoma were significantly higher than those in adjacent normal tissues and in IPMN tissue with low-to high-grade dysplasia. KPNA2 expression correlated with pathological malignancy and Ki-67 labeling index and KPNA2 and Ki-67 expression was co-localized in nuclei. E2F were co-localized with KPNA2 in the IPMN tissues with high expression of KPNA2. KPNA2 expression was enhanced in the invasion front and in proliferating Ki-67-positive cells. In addition, KPNA2 expression in IPMN tissues was associated with older age, dilation of main pancreatic duct diameter, the presence of nodules, and histological type. CONCLUSION KPNA2 expression is associated with carcinogenesis of IPMN through the adenoma-carcinoma sequence.