Shinichi Hirooka

DYRK2 regulates epithelial-mesenchymal-transition and chemosensitivity through Snail degradation in ovarian serous adenocarcinoma

Epithelial-mesenchymal-transition (EMT) plays essential roles in ovarian cancer invasion, metastasis, and drug resistance. A hallmark of EMT is the loss of E-cadherin, which is regulated by Snail. Recently, it was shown that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls Snail degradation in breast cancer. The aim of this study is to clarify whether DYRK2 regulates EMT through Snail degradation in ovarian serous adenocarcinoma (SA). Expression of DYRK2 and Snail in two pairs of cisplatin-resistant and the original cisplatin-sensitive ovarian cancer cell line were analyzed by immunoblotting and real-time RT-PCR analysis. Morphological change, invasion ability, and chemosensitivity were evaluated by using DYRK2 stable knockdown cell line in 2008 (2008 shDYRK2). Immunohistochemical analyses for DYRK2 and Snail were performed with surgical specimens. The correlations between the expression of these proteins and the clinicopathological parameters, including prognosis, were determined. Moreover, we conducted a hypodermic administration test in nude mice and examined reproductive and cisplatin response activities. DYRK2 protein expression was posttranslationally reduced in cisplatin-resistant SA cell lines. 2008 shDYRK2 showed mesenchymal phenotype and resistant to cisplatin. Immunohistochemistry demonstrated that DYRK2 expression inversely correlated with Snail expression, and reduced expression of DYRK2 was associated with shorter overall survival in SA. DYRK2 may regulate EMT through Snail degradation in ovarian SA and might be a predictive marker for a favorable prognosis in the treatment of this cancer.

Dual‐specificity tyrosine‐regulated kinase 2 is a suppressor and potential prognostic marker for liver metastasis of colorectal cancer

Colorectal cancer is a common cancer and a leading cause of cancer‐related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial–mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) controls epithelial–mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2‐overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease‐free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer.

Simplified criteria for diagnosing superficial esophageal squamous neoplasms using Narrow Band Imaging magnifying endoscopy

AIM To simplify the diagnostic criteria for superficial esophageal squamous cell carcinoma (SESCC) on Narrow Band Imaging combined with magnifying endoscopy (NBI-ME). METHODS This study was based on the post-hoc analysis of a randomized controlled trial. We performed NBI-ME for 147 patients with present or a history of squamous cell carcinoma in the head and neck, or esophagus between January 2009 and June 2011. Two expert endoscopists detected 89 lesions that were suspicious for SESCC lesions, which had been prospectively evaluated for the following 6 NBI-ME findings in real time: “intervascular background coloration”; “proliferation of intrapapillary capillary loops (IPCL)”; and “dilation”, “tortuosity”, “change in caliber”, and “various shapes (VS)” of IPCLs (i.e., Inoue’s tetrad criteria). The histologic examination of specimens was defined as the gold standard for diagnosis. A stepwise logistic regression analysis was used to identify candidates for the simplified criteria from among the 6 NBI-ME findings for diagnosing SESCCs. We evaluated diagnostic performance of the simplified criteria compared with that of Inoue’s criteria. RESULTS Fifty-four lesions (65%) were histologically diagnosed as SESCCs and the others as low-grade intraepithelial neoplasia or inflammation. In the univariate analysis, proliferation, tortuosity, change in caliber, and VS were significantly associated with SESCC (P < 0.01). The combination of VS and proliferation was statistically extracted from the 6 NBI-ME findings by using the stepwise logistic regression model. We defined the combination of VS and proliferation as simplified dyad criteria for SESCC. The areas under the curve of the simplified dyad criteria and Inoue’s tetrad criteria were 0.70 and 0.73, respectively. No significant difference was shown between them. The sensitivity, specificity, and accuracy of diagnosis for SESCC were 77.8%, 57.1%, 69.7% and 51.9%, 80.0%, 62.9% for the simplified dyad criteria and Inoue’s tetrad criteria, respectively. CONCLUSION The combination of proliferation and VS may serve as simplified criteria for the diagnosis of SESCC using NBI-ME.

Clinicopathological characteristics of duodenal epithelial neoplasms: Focus on tumors with a gastric mucin phenotype (pyloric gland-type tumors)

Objective Epithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors. Materials and methods Among duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands. Results As for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p<0.01). PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands. Conclusions About 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands.

Impairment of DYRK2 augments stem-like traits by promoting KLF4 expression in breast cancer

Whereas accumulating studies have supported the cancer stem cell theory, a specific therapy targeting a cancer stem cell subpopulation has not been established. Here, we show that dual-specificity tyrosine phosphorylation-kinase 2 (DYRK2) is a novel negative regulator for formation of breast cancer stem cells. Downregulation of DYRK2 promotes cancer stem-like traits in vitro, tumourigenesis in vivo and the proportion of the cancer stem cell population in human breast cancer tissues. We found that Krupple-like factor 4 (KLF4) serves as a key mediator of DYRK2’s control over the cancer stem phenotype. Reduced DYRK2 expression increases KLF4 expression, which induces cancer stem-like properties. We identified androgen receptor (AR) as a transcription factor binding to the KLF4 promoter region; this process is dependent on DYRK2 kinase activity. Our findings delineate a mechanism of cancer stem cell regulation by the DYRK2–AR–KLF4 axis in breast cancer. Targeting of this pathway may be a promising strategy against breast cancer stem cells.

Downregulation of dual-specificity tyrosine-regulated kinase 2 promotes tumor cell proliferation and invasion by enhancing cyclin-dependent kinase 14 expression in breast cancer

Tumor progression is the main cause of death in patients with breast cancer. Accumulating evidence suggests that dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) functions as a tumor suppressor by regulating cell survival, differentiation, proliferation and apoptosis. However, little is known about the mechanisms of transcriptional regulation by DYRK2 in cancer progression, particularly with respect to cancer proliferation and invasion. Here, using a comprehensive expression profiling approach, we show that cyclin‐dependent kinase 14 (CDK14) is a target of DYRK2. We found that reduced DYRK2 expression increases CDK14 expression, which promotes cancer cell proliferation and invasion in vitro, in addition to tumorigenicity in vivo. CDK14 and DYRK2 expression inversely correlated in human breast cancer tissues. We further identified androgen receptor (AR) as a candidate of DYRK2‐dependent transcription factors regulating CDK14. Taken together, our findings suggest a mechanism by which DYRK2 controls CDK14 expression to regulate tumor cell proliferation and invasion in breast cancer. Targeting of this pathway may be a promising therapeutic strategy for treating breast cancer.

Reply to the letter to the editor: Lymph node metastasis of adenocarcinoma and different definitions of sm1 cancer in the esophagus

Ryu Ishihara • Tsuneo Oyama • Seiichiro Abe • Hiroaki Takahashi • Hiroyuki Ono • Junko Fujisaki • Mitsuru Kaise • Kenichi Goda • Kenro Kawada • Tomoyuki Koike • Manabu Takeuchi • Rie Matsuda • Dai Hirasawa • Masayoshi Yamada • Junichi Kodaira • Masaki Tanaka • Masami Omae • Akira Matsui • Takashi Kanesaka • Akiko Takahashi • Shinichi Hirooka • Masahiro Saito • Yosuke Tsuji • Yuki Maeda • Hiroharu Yamashita • Ichiro Oda • Yasuhiko Tomita • Takashi Matsunaga • Shuji Terai • Soji Ozawa • Tatsuyuki Kawano • Yasuyuki Seto

Features of sinonasal hemangioma: A retrospective study of 31 cases

OBJECTIVE Although hemangiomas are common lesions of the head and neck, sinonasal hemangiomas are rare. The purpose of this study was to analyze the clinical features (sex, age, symptoms, and size and anatomical location of the lesion) and the histological findings of sinonasal hemangioma cases, to assess preoperative transarterial embolization, and to evaluate the outcome (recurrence or no recurrence) of endoscopic sinus surgery. METHODS Clinical records of 31 patients who underwent endoscopic sinus surgery for resection of sinonasal hemangioma between January 2010 and June 2015 were retrospectively reviewed. RESULTS The study group consisted of 19 men and 12 women. Mean age was 53.3±15.9years. The principal symptom was epistaxis (81%). Mean tumor size was 12.6±8.2mm. The most common origin of hemangioma was the inferior turbinate (45%), followed by the nasal septum (39%), and, in both locations, the origin had a tendency to be located in the anterior portion. Thirty-one specimens were histologically categorized as 9 cavernous hemangiomas and 22 capillary hemangiomas. Preoperative transarterial embolization was performed in 2 cases. Only one recurrence was observed among 31 cases. In the recurrent case, the hemangioma of the nasal septum was resected during pregnancy. CONCLUSION According to our results, the transnasal endoscopic approach can be useful for the resection of sinonasal hemangioma. However, sinonasal hemangioma in connection with pregnancy must be addressed with care to decide the appropriate time for treatment.

Pulmonary and retroperitoneal lesions induced by methotrexate-associated lymphoproliferative disorder in a patient with rheumatoid arthritis

A 78-year-old man had fatigue and appetite loss for 5 months. He had been receiving low-dose methotrexate for rheumatoid arthritis. Computed tomography revealed multiple pulmonary infiltrations and muddiness of the fatty tissue surrounding the right kidney, ureter wall thickening, and hydroureter/nephrosis, which were suspected retroperitoneal fibrosis. Lung biopsy revealed polymorphic/lymphoplasmacytic lymphoproliferative disorder. Methotrexate withdrawal resulted in spontaneous regression. Therefore, retroperitoneal lesion may account for the diagnosis as having retroperitoneal lymphoproliferative disorder, not retroperitoneal fibrosis.