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ABSTRACT: Abstract There is accumulating evidence that pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, promote the progression of pancreatic cancer. The interactions between PSCs and pancreatic cancer have attracted substantial attention as a novel therapeutic target for the treatment of pancreatic cancer. We examined here the effects of olmesartan, an angiotensin II type I receptor blocker, on pancreatic cancer-associated fibrosis using a subcutaneous tumor model developed by co-injection of pancreatic cancer cells with PSCs in nude mice. Co-injection of pancreatic cancer cells AsPC-1 with PSCs increased the size of tumors compared with AsPC-1 cells alone. Olmesartan administrated at 10 mg/kg in drinking water inhibited the growth of subcutaneous tumors derived from the co-injection, but not those derived from mono-injection. This effect was accompanied by decreased expression of α-smooth muscle actin (a marker of activated PSCs) and collagen deposition. The inhibitory effect of olmesartan was also observed even if it was administrated after significant development of subcutaneous tumors. In addition, olmesartan decreased cell growth and type I collagen production in PSCs in vitro. These results suggest that olmesartan inhibited the growth of tumors by targeting stellate cell activities, and that olmesartan might be useful as an anti-fibrosis therapy in pancreatic cancer.
Scandinavian journal of gastroenterology 03/2013; · 2.08 Impact Factor
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ABSTRACT: Islet fibrosis, pancreatic β-cell dysfunction, and β-cell apoptosis are features of pancreatic diabetes and type 2 diabetes; however, the underlying mechanisms remain largely unknown. We hypothesized that pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, might affect the phenotype of pancreatic β-cells. α-smooth muscle actin (a marker of activated PSC)-positive cells were found within and around the fibrotic islets. Indirect co-culture with PSCs reduced insulin expression and induced apoptosis in RIN-5F pancreatic β-cells. Induction of β-cell apoptosis was associated with activation of the caspase pathway and mitochondrial depolarization. Diphenylene iodonium, an inhibitor of PSC activation, inhibited islet fibrosis and protected islets in vivo. Our findings suggest a novel mechanism linking PSCs, islet fibrosis, and diabetes mellitus.
Biochemical and Biophysical Research Communications 03/2013; · 2.48 Impact Factor
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Nihon Naika Gakkai Zasshi 12/2012; 101(12):3510-2.
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Shin Hamada,
Kennichi Satoh,
Shin Miura,
Morihisa Hirota,
Atsushi Kanno,
Atsushi Masamune, Kazuhiro Kikuta,
Kiyoshi Kume,
Jun Unno,
Shinichi Egawa,
Fuyuhiko Motoi,
Michiaki Unno,
Tooru Shimosegawa
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ABSTRACT: Invasive ductal adenocarcinoma (IDA) of the pancreas manifests poor prognosis due to the early invasion and distant metastasis. In contrast, intraductal papillary mucinous adenoma or carcinoma (IPMA or IPMC) reveals better clinical outcomes. Various molecular mechanisms contribute to these differences but entire picture is still unclear. Recent researches emphasized the important role of miRNA in biological processes including cancer invasion and metastasis. We previously described that miR-126 is down-regulated in IDA compared with IPMA or IPMC, and miR-126 regulates the expression of invasion related molecule disintegrin and metalloproteinase domain-containing protein 9 (ADAM9). Assessing the difference of miRNA expression profiles of IDA, IPMA and IPMC, we newly identified miR-197 as an up-regulated miRNA specifically in IDA. Expression of miR-197 in pancreatic cancer cells resulted in the induction of epithelial-mesenchymal transition (EMT) along with the down-regulation of p120 catenin which is a putative target of miR-197. Direct interaction between miR-197 and p120 catenin mRNA sequence was confirmed by 3'UTR assay, and knockdown of p120 catenin recapitulated EMT induction in pancreatic cancer cells. In situ hybridization of miR-197 and immunohistochemistry of p120 catenin showed mutually exclusive patterns suggesting pivotal role of miR-197 in the regulation of p120 catenin. This miR-197 / p120 catenin axis could be a novel therapeutic target. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
Journal of Cellular Physiology 11/2012; · 3.87 Impact Factor
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Atsushi Kanno,
Kazuyuki Ishida,
Shin Hamada,
Fumiyoshi Fujishima,
Jun Unno,
Kiyoshi Kume, Kazuhiro Kikuta,
Morihisa Hirota,
Atsushi Masamune,
Kennichi Satoh,
Kenji Notohara,
Tooru Shimosegawa
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ABSTRACT: It is controversial whether EUS-guided FNA by using 22-gauge (G) needles is useful for the diagnosis or evaluation of autoimmune pancreatitis (AIP).
To evaluate the usefulness of EUS-FNA by 22-G needles for the histopathological diagnosis of AIP.
A retrospective study.
Single academic center.
A total of 273 patients, including 25 with AIP, underwent EUS-FNA and histological examinations.
EUS-FNA by using 22-G needles provided adequate tissue samples for histopathological evaluation because more than 10 high-power fields were available for evaluation in 20 of 25 patients (80%). The mean immunoglobulin G4-positive plasma cell count was 13.7/high-power field. Obliterative phlebitis was observed in 10 of 25 patients (40%). In the context of the International Consensus Diagnostic Criteria for AIP, 14 and 6 of 25 patients were judged to have level 1 (positive for 3 or 4 items) and level 2 (positive for 2 items) histological findings, respectively, meaning that 20 of 25 patients were suggested to have lymphoplasmacytic sclerosing pancreatitis based on the International Consensus Diagnostic Criteria. The diagnosis in 1 patient was type 2 AIP because a granulocytic epithelial lesion was identified in this patient.
A retrospective study with a small number of patients.
The results of this study suggest that EUS-FNA by using 22-G needles provides tissue samples adequate for histopathological evaluation and greatly contributes to the histological diagnosis of AIP.
Gastrointestinal endoscopy 09/2012; 76(3):594-602. · 6.71 Impact Factor
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Atsushi Masamune,
Noriaki Suzuki, Kazuhiro Kikuta,
Hiroyuki Ariga,
Shintaro Hayashi,
Tetsuya Takikawa,
Kiyoshi Kume,
Shin Hamada,
Morihisa Hirota,
Atsushi Kanno,
Shinichi Egawa,
Michiaki Unno,
Tooru Shimosegawa
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ABSTRACT: OBJECTIVES: Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. Connexins (Cxs) allow direct intercellular communications as components of gap junction but also play important roles in the regulation of cell proliferation, cell differentiation, and tissue development. We here examined the expression of Cxs and Cx-mediated regulation of cell functions in PSCs. METHODS: Human PSCs were isolated from patients undergoing operation for chronic pancreatitis or pancreatic cancer. The expression of Cxs was examined by reverse transcription polymerase chain reaction, Western blotting, and immunofluorescent staining. The roles of Cxs in PSC functions were examined by using carbenoxolone, a broad-spectrum Cx inhibitor, and small interfering RNA for Cx43. RESULTS: Human activated PSCs expressed a variety of Cxs including Cx43 both in vitro and in vivo. Carbenoxolone inhibited platelet-derived growth factor-BB-induced proliferation and migration, and type I collagen expression in PSCs. In addition, carbenoxolone inhibited the activation of quiescent PSCs to a myofibroblastlike phenotype. Decreased Cx43 expression by small interfering RNA resulted in decreased proliferation and type I collagen expression. CONCLUSIONS: Pancreatic stellate cells expressed a variety of Cxs. Connexins, especially Cx43, might regulate the cell functions and activation of PSCs.
Pancreas 08/2012; · 2.39 Impact Factor
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Morihisa Hirota,
Kennichi Satoh, Kazuhiro Kikuta,
Atsushi Masamune,
Kiyoshi Kume,
Shin Hamada,
Akihiko Satoh,
Atsushi Kanno,
Jun Unno,
Hiromichi Ito,
Hiroyuki Ariga,
Tooru Shimosegawa
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ABSTRACT: The usefulness of early severity assessment of acute pancreatitis (AP) by contrast-enhanced computed tomography (CECT) was investigated.
Data were obtained from a 2007 nationwide survey in Japan. Clinical data of 983 patients with AP were analyzed. All were examined by CECT on the day of admission.
Early findings of CECT demonstrated that low enhanced pancreatic parenchyma (LEPP) was associated with the incidence of organ failure (OF), multiple OF, and infectious complications as well as mortality (P < 0.0001). Next, patients were further divided into 4 groups according to the CECT findings, which focused on the LEPP and peripancreatic collections (PPCs). The LEPP/PPC (+/+) group was characterized as high morbidity and high mortality. The incidence of OF (28.2%), multiple OF (15.5%), and mortality (11.4%) in patients assigned to the (+/+) group was significantly higher than in those assigned to the other groups. The incidence of infectious complications was significantly higher in patients assigned to the (+/+) group (16.7%), the (+/-) group (9.0%), and the (-/+) group (7.0%) than those assigned to the (-/-) group (1.8%).
The detection of LEPP and PPC was a useful CECT finding for the early assessment of the severity of AP.
Pancreas 06/2012; 41(7):1099-104. · 2.39 Impact Factor
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ABSTRACT: The patient was a 73 year old man for whom surgery under general anesthesia was difficult to perform because of pulmonary emphysema. In April 2003, he visited our hospital complaining of epigastralgia and dorsal pain, and was admitted under a diagnosis of acute exacerbation of chronic pancreatitis. In 2005, acute cholangitis concomitantly developed with acute exacerbation of chronic pancreatitis, for which a plastic stent was placed in the common bile duct. Cholangitis repeatedly developed every 2-3 months thereafter, and admission was required each time to exchange the stent. Surgery was considered but not applicable because of his poor respiratory function, and a partially covered self-expandable metallic stent was inevitably placed in the bile duct. Ten months later, an aberration of the metallic stent in the bile duct occurred, but it was dealt with by placing an additional metallic stent, and no cholangitis or pancreatitis developed until the patient died of respiratory insufficiency 3 years later. Placement of a covered self-expandable metallic stent might be an option for the treatment of benign biliary stricture, especially in patients at high risk from surgery.
Digestive Endoscopy 05/2012; 24 Suppl 1:43-8. · 1.19 Impact Factor
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Kiyoshi Kume,
Atsushi Masamune,
Hiroyuki Ariga,
Shintaro Hayashi,
Tetsuya Takikawa,
Shin Miura,
Noriaki Suzuki, Kazuhiro Kikuta,
Shin Hamada,
Morihisa Hirota,
Atsushi Kanno,
Tooru Shimosegawa
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ABSTRACT: BACKGROUND: The serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI), is a peptide secreted by pancreatic acinar cells. Genetic studies have shown an association between SPINK1 gene variants and chronic pancreatitis or recurrent acute pancreatitis. The aim of this study was to clarify whether the SPINK1 variants affect the level of serum PSTI. METHODS: One hundred sixty-three patients with chronic pancreatitis or recurrent acute pancreatitis and 73 healthy controls were recruited. Serum PSTI concentrations were determined with a commercial radioimmunoassay kit. RESULTS: Ten patients with the p.N34S variant, 7 with the IVS3+2T>C variant, two with both the p.N34S and the IVS3+2T>C variants, and one with the novel missense p.P45S variant in the SPINK1 gene were identified. The serum PSTI level in patients with no SPINK1 variants was 14.3 ± 9.6 ng/ml (mean ± SD), and that in healthy controls was 10.7 ± 2.2 ng/ml. The PSTI level in patients carrying the IVS3+2T>C variant (5.1 ± 3.4 ng/ml), but not in those with the p.N34S variant (8.9 ± 3.5 ng/ml), was significantly lower than that in the patients without the SPINK1 variants and the healthy controls. The serum PSTI level in the patient with the p.P45S variant was 4.9 ng/ml. Low levels of serum PSTI (<6.0 ng/ml) showed sensitivity of 80 %, specificity of 97 %, and accuracy of 96 % in the differentiation of IVS3+2T>C and p.P45S carriers from non-carriers. CONCLUSION: Serum PSTI levels were decreased in patients with the IVS3+2T>C and p.P45S variants of the SPINK1 gene.
Journal of Gastroenterology 04/2012; · 4.16 Impact Factor
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ABSTRACT: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called "cancer stem cells", within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the "stemness" of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.
Biochemical and Biophysical Research Communications 04/2012; 421(2):349-54. · 2.48 Impact Factor
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ABSTRACT: To clarify the clinicoepidemiological features of autoimmune pancreatitis (AIP) in Japan, the nationwide survey was conducted.
Patients with AIP who had visited the selected hospitals in 2007 were surveyed. Autoimmune pancreatitis was diagnosed according to the Japanese clinical diagnostic criteria 2006. The study consisted of 2-stage surveys: the number of patients with AIP was estimated by the first questionnaire and their clinical features were assessed by the second questionnaire.
The estimated total number of AIP patients in 2007 was 2790 (95% confidence interval, 2540-3040), with an overall prevalence rate of 2.2 per 100,000 populations. The number of patients, who were newly diagnosed as AIP, was estimated to be 1120 (95% confidence interval, 1000-1240), with an annual incidence rate of 0.9 per 100,000 populations. Sex ratio (male to female) was 3.7, and the mean (SD) age was 63.0 (11.4) years. Among the 546 patients whose clinical information was obtained, 87.6% of the patients presented high serum immunoglobulin G4 levels (≥ 135 mg/dL), and 83% received steroid therapy.
The data represent the current clinical features of AIP in Japan. From the results, most AIP patients in Japan can be categorized to type 1 AIP according to the recent classification of AIP.
Pancreas 03/2012; 41(6):835-9. · 2.39 Impact Factor
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Morihisa Hirota,
Tooru Shimosegawa,
Atsushi Masamune, Kazuhiro Kikuta,
Kiyoshi Kume,
Shin Hamada,
Yasuyuki Kihara,
Akihiko Satoh,
Kenji Kimura,
Ichiro Tsuji,
Shinichi Kuriyama
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ABSTRACT: A nationwide survey was conducted to clarify the epidemiological features of patients with chronic pancreatitis (CP) in Japan.
Two sequential surveys were conducted. In the first survey, both the prevalence and incidence of CP in Japan in 2007 were estimated by a questionnaire, which was mailed to 3027 randomly chosen Japanese facilities. In the second survey, the second questionnaire was then mailed to 1110 facilities selected by the first survey to clarify the clinicoepidemiological features of the patients.
The estimated annual prevalence of CP was 36.9 per 100,000; 53.2 in males and 21.2 in females. The estimated annual incidence was 11.9 per 100,000. The prevalence and the incidence of CP gradually increased in Japan as compared to former surveys. The sex ratio (male/female) of definitive and probable CP patients was 4.5, with a mean age of 59.4 years; 59.2 years in males and 60.2 years in females. Alcoholic (69.7%) was most the common and idiopathic (21.0%) was the second most common cause of CP. The proportion of alcoholic CP increased as compared to the 55.5% found in 1994. The clinical features of overall Japanese patients with CP were: abdominal pain (60.6%), malabsorbtion (12.2%), diabetes mellitus (39.7%) and pancreatolithiasis (75.7%). Alcoholic patients were characterized by high morbidity as compared to nonalcoholic patients: abdominal pain (alcoholic 65.0% vs nonalcoholic 53.0%, p < 0.0001), diabetes mellitus (44.8% vs 31.4%, p < 0.0001) and pancreatolithiasis (84.0% vs 60.8%, p < 0.0001).
The prevalence and the incidence of CP, especially alcoholic CP, have been increasing in Japan.
Pancreatology 03/2012; 12(2):79-84. · 1.99 Impact Factor
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ABSTRACT: Chronic pancreatitis (CP) has been considered an intractable inflammatory disease that is progressive and irreversible after definite structural changes appear in the pancreas. The Japanese diagnostic criteria for CP were revised in 2009. One of the reasons for this revision was to define a diagnostic criterion for the early phase of CP (early CP) to improve a patient's clinical outcome, because the disease progression might be reversed in this phase by a therapeutic intervention. However, the clinical features and outcome of early CP remain largely unknown, and the diagnostic reliability of early CP needs to be verified. Here, we show two patients who met the diagnostic criteria of early CP and then progressed to the advanced, late phase of CP (definite CP). A 64-year-old man with recurrent acute pancreatitis was diagnosed as early CP and later progressed to definite CP with multiple pancreatic calcifications at the age of 69. The etiology of CP in this patient was thought to be idiopathic. The other patient was a 57-year-old man with alcohol abuse (ethanol consumption > 120 g/day). He was diagnosed as early CP and then rapidly progressed to definite CP without any acute attack. He could not remain abstinent after the diagnosis of early CP. In the present report, we retrospectively demonstrated distinct clinical features of the two patients, both of whom were diagnosed as early CP first and then progressed to definite CP. Thus, our findings support the disease concept of early CP and also suggest the validity of the revised Japanese criteria for the diagnosis of early CP.
The Tohoku Journal of Experimental Medicine 01/2012; 228(3):173-80. · 1.24 Impact Factor
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ABSTRACT: The epithelial-mesenchymal transition (EMT) is a critical step for pancreatic cancer cells as an entry of metastatic disease. Wide variety of cytokines and signaling pathways are involved in this complex process while the entire picture is still cryptic. Recently, miRNA was found to regulate cellular function including EMT by targeting multiple mRNAs. We conducted comprehensive analysis of miRNA expression profiles in invasive ductal adenocarcinoma (IDA), intraductal papillary mucinous adenoma, intraductal papillary mucinous carcinoma, and human pancreatic cancer cell line to elucidate essential miRNAs which regulate invasive growth of pancreatic cancer cells. Along with higher expression of miR-21 which has been shown to be highly expressed in IDA, reduced expression of miR-126 in IDA and pancreatic cancer cell line was detected. The miR-126 was found to target ADAM9 (disintegrin and metalloproteinase domain-containing protein 9) which is highly expressed in pancreatic cancer. The direct interaction between miR-126 and ADAM9 mRNA was confirmed by 3' untranslated region assay. Reexpression of miR-126 and siRNA-based knockdown of ADAM9 in pancreatic cancer cells resulted in reduced cellular migration, invasion, and induction of epithelial marker E-cadherin. We showed for the first time that the miR-126/ADAM9 axis plays essential role in the inhibition of invasive growth of pancreatic cancer cells.
Molecular Cancer Research 11/2011; 10(1):3-10. · 4.29 Impact Factor
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Morihisa Hirota,
Tohru Asakura,
Atsushi Kanno, Kazuhiro Kikuta,
Kiyoshi Kume,
Shin Hamada,
Jun Unno,
Hiromichi Ito,
Hiroyuki Ariga,
Atsushi Masamune,
Kennichi Satoh,
Fuyuhiko Motoi,
Shinichi Egawa,
Michiaki Unno,
Tooru Shimosegawa
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ABSTRACT: The aim of this study was to compare the benefits between endoscopic drainage and surgical drainage of the pancreatic duct for patients with chronic calcified pancreatitis.
A total of 68 patients were classified into endoscopic (n = 34) or surgical (n = 34) treatment groups. Patients receiving endoscopic treatment were further divided into 2 subgroups: a short-period group, patients who could discontinue serial pancreatic stenting within 1 year (n = 19); and a long-period group, patients who needed pancreatic drainage by serial endoscopic stenting for more than 1 year (n = 15). The medical records of these patients were retrospectively analyzed.
Hospital stays, frequency of hospitalizations, and medical expense were similar between the short-period endoscopic treatment group and surgery group. On the other hand, patients in the long-period endoscopic treatment group required significantly longer hospital stays, more frequent hospitalizations, and had higher medical expenses than the short-period endoscopic treatment group as well as than the surgery group.
Patients who underwent serial endoscopic stenting for more than 1 year showed no benefit compared with surgical treatment in terms of the frequency of hospital stays and medical costs.
Pancreas 08/2011; 40(6):946-50. · 2.39 Impact Factor
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Morihisa Hirota,
Masashi Tsuda,
Yoshihisa Tsuji,
Atsushi Kanno, Kazuhiro Kikuta,
Kiyoshi Kume,
Shin Hamada,
Jun Unno,
Hiromichi Ito,
Hiroyuki Ariga,
Tsutomu Chiba,
Atsushi Masamune,
Kennichi Satoh,
Tooru Shimosegawa
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ABSTRACT: The aim of this study was to clarify the pancreatic blood perfusion in patients with autoimmune pancreatitis (AIP) and the changes after steroid treatment.
Perfusion computed tomography was performed in 11 patients with AIP and 12 control subjects. Pancreatic volumetric blood flow (F(V)), volume of distribution (V(D)), and blood transit time τ were determined from a single-compartment kinetic model. Nine patients with AIP were reexamined by perfusion computed tomography after corticosteroid administration.
The pancreatic F(V) values of the 11 patients with AIP (82.7/min) were significantly lower than those of control subjects (163.5/min, P = 0.0006). On the other hand, the pancreatic V(D) and τ values were not significantly different between AIP and normal. After steroid treatment, the F(V) values of 9 reexamined patients with AIP (76.2/min) were significantly elevated (109.8/min, P = 0.0391). However, the changes of the values after the treatment differed in degree among individuals. The values of 4 patients were dramatically elevated to greater than 100/min, whereas those of 4 other patients did not improve well. The value of the remaining patient whose initial F(V) value was normal (168.09/min) did not change after the treatment.
Pancreatic volumetric perfusion was attenuated in AIP patients. The perfusion was improved after the steroid treatment.
Pancreas 06/2011; 40(8):1295-301. · 2.39 Impact Factor
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ABSTRACT: A nationwide epidemiological survey was conducted to estimate the number of patients treated for acute pancreatitis (AP) in 2007 in Japan and to clarify the clinicoepidemiological features of AP.
In the first survey, a simple questionnaire was used to inquire about the number of patients with AP who visited the hospital in the year 2007. This questionnaire was directly mailed to the heads of 3027 facilities. The second questionnaire was forwarded to those facilities from which patients with AP were reported on the first questionnaire.
The estimated total number of patients treated for AP in 2007 was 57,560 (95% confidence interval, 48,571-66,549), with an overall prevalence rate of 45.1 per 100,000 population. The sex ratio (male-female) of the patients was 2.0, with a mean age of 56.6 years in men and 64.6 years in women. Alcoholic AP was most common in men and gallstone AP in women. The overall mortality rate of AP was 1.9% and, in severe cases, 8.0%.
The number of patients with AP increased about 3-fold during this decade (19,500 in 1998 to 57,560 in 2007), and the mortality rate of AP was reduced from 7.4% in 1998 and 2.9% in 2003 to 1.9% in 2007.
Pancreas 05/2011; 40(4):503-7. · 2.39 Impact Factor
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ABSTRACT: Pancreatic cancer is one of the life-threatening cancers due to the difficulty in the curative surgery and resistance against conventional therapeutic strategies. Recent studies indicated that cancer stem cells, which exist as a small number of cells within the entire cancer tissue, contribute to the disease progression. Cancer stem cells reveal resistance against conventional chemotherapy, which is derived from the high-expression of multiple transporter genes. Our previous study demonstrated the aggravating role of the homeobox gene MSX2 as an inducer of epithelial-mesenchymal transition, and MSX2 turned out to correlate with the chemoresistance in the current study. Comprehensive analysis of the MSX2-target gene has identified ABCG2 as the responsible gene. Since previous studies reported the pivotal role of ABCG2 as a determining factor of cancer stem cells, the detailed regulatory mechanism of ABCG2 expression by MSX2 was investigated. As a result, the MSX2 expression level in each cell line well correlated with the ABCG2 expression level, and alteration of the MSX2 expression level by over-expression or siRNA-based knockdown affected the ABCG2 expression accordingly. Finally, we identified the functional cooperation of MSX2 and SP1 in the transcriptional regulation of ABCG2 via the SP1 binding elements within the ABCG2 promoter. These findings clarified the intriguing regulatory mechanism of the cancer stem cell-related gene, and will delineate a novel therapeutic target in pancreatic cancer.
Journal of Cellular Physiology 04/2011; 227(2):729-38. · 3.87 Impact Factor
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ABSTRACT: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Because epithelial-mesenchymal transition (EMT) plays a critical role in the progression of pancreatic cancer, we hypothesized that PSCs promote EMT in pancreatic cancer cells. Panc-1 and SUIT-2 pancreatic cancer cells were indirectly co-cultured with human PSCs isolated from patients undergoing operation for pancreatic cancer. The expression of epithelial and mesenchymal markers was examined by real-time PCR and immunofluorescent staining. The migration of pancreatic cancer cells was examined by scratch and two-chamber assays. Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and a scattered, fibroblast-like appearance. The expression of E-cadherin, cytokeratin 19, and membrane-associated β-catenin was decreased, whereas vimentin and Snail (Snai-1) expression was increased more in cancer cells co-cultured with PSCs than in mono-cultured cells. The migration of pancreatic cancer cells was increased by co-culture with PSCs. The PSC-induced decrease of E-cadherin expression was not altered by treatment with anti-TGF-β-neutralizing antibody, excluding a central role of TGF-β in this process. In conclusion, PSCs promoted EMT in pancreatic cancer cells suggesting a novel mechanism by which PSCs contribute to the aggressive behavior of pancreatic cancer cells.
Biochemical and Biophysical Research Communications 11/2010; 403(3-4):380-4. · 2.48 Impact Factor
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ABSTRACT: Activated pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. Recent studies have suggested a role of IL-33, a newly identified IL-1 family member, in fibrosis. We here examined the expression of IL-33 and the IL-33-mediated regulation of cell functions in PSCs. PSCs were isolated from human and rat pancreas tissues. The expression of IL-33 was examined by Western blotting, PCR, ELISA, and immunostaining. The roles of IL-33 in the regulation of PSC functions were examined by using recombinant IL-33 and small interfering RNA. Activated PSCs expressed IL-33 in the nucleus, and the expression was increased by IL-1β, TNF-α, PDGF-BB, and IFN-γ, but not TGF-β1. Nuclear IL-33 expression was also observed in the pancreatic acinar and ductal cells. IL-1β induced IL-33 expression mainly through the activation of NF-κB and ERK pathways and partially through that of p38 MAP kinase, whereas PDGF-BB induced IL-33 expression mainly through the activation of ERK pathway. PSCs expressed soluble ST2, ST2L, and IL-1RAcP, but the expression level of ST2L was relatively low. Recombinant IL-33 did not stimulate key cell functions of PSCs. Decreased IL-33 expression by small interfering RNA resulted in decreased proliferation in response to PDGF-BB. In conclusion, activated PSCs expressed IL-33 in the nucleus. IL-33 might regulate the PDGF-induced proliferation in PSCs.
AJP Gastrointestinal and Liver Physiology 10/2010; 299(4):G821-32. · 3.43 Impact Factor
