Regulators of Epithelial Sodium Channels in Aldosterone-Sensitive Distal Nephrons (ASDN): Critical Roles of Nedd4L/Nedd4-2 and Salt-Sensitive Hypertension.

Ubiquitination is a representative, reversible biological process of the post-translational modification of various proteins with multiple catalytic reaction sequences, including ubiquitin itself, in addition to E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, E3 ubiquitin ligase, deubiquitinating enzymes, and proteasome degradation. The ubiquitin-proteasome system is known to play a pivotal role in various molecular life phenomena, including the cell cycle, protein quality, and cell surface expressions of ion-transporters. As such, the failure of this system can lead to cancer, neurodegenerative diseases, cardiovascular diseases, and hypertension. This review article discusses Nedd4-2/NEDD4L, an E3-ubiquitin ligase involved in salt-sensitive hypertension, drawing from detailed genetic dissection analysis and the development of genetically engineered mice model. Based on our analyses, targeting therapeutic regulations of ubiquitination in the fields of cardio-vascular medicine might be a promising strategy in future. Although the clinical applications of this strategy are limited, compared to those of kinase systems, many compounds with a high pharmacological activity were identified at the basic research level. Therefore, future development could be expected.

Kanagawa Investigation of the Total Check-up Data from the National database (KITCHEN): protocol for data-driven population-based repeated cross-sectional and 6-year cohort studies.

INTRODUCTION: The unmitigated incidence of cardiometabolic diseases, such as type 2 diabetes and metabolic syndrome, has gained attention in Japan. 'Big data' can be useful to clarify conflicting observations obtained from studies with small samples and about rare conditions that are often neglected. We epidemiologically address these issues using data from health check-ups conducted in Kanagawa Prefecture, the prefecture with the second largest population in Japan, in the Kanagawa Investigation of the Total Check-up Data from the National Database (KITCHEN). METHODS AND ANALYSIS: This research consists of a series of population-based cross-sectional studies repeated from 2008-2014 and 6-year cohort studies. Since 2017, we have reviewed the data of people living in Kanagawa Prefecture who underwent a health check-up mainly for general health and the prevention of metabolic syndrome. The sample size ranges from 1.2 million to 1.8 million people in the cross-sectional studies and from 370 000 to 590 000 people in the cohort studies. These are people aged 40-74 years, whose clinical parameters were measured and who responded individually to a questionnaire. We investigate potential associations and causalities of various aetiologies, including diabetes and metabolic syndrome, using clinical data and lifestyle information. With multidisciplinary analysis, including data-driven analysis, we expect to obtain a wide range of novel findings, to confirm indeterminate previous findings, especially in terms of cardiometabolic disease, and to provide new perspectives for human health promotion and disease prevention. ETHICS AND DISSEMINATION: Ethical approval was received from the Ethics Committee of Kanagawa University of Human Services (10-43). The protocol was approved in December 2016 by the Japanese Ministry of Health, Labour and Welfare (No. 121). The study results will be disseminated through open platforms including journal articles, relevant conferences and seminar presentations.

Fibrotic focus: An important parameter for accurate prediction of a high level of tumor-associated macrophage infiltration in invasive ductal carcinoma of the breast.

Our group and others have previously reported that a fibrotic focus is a very useful histological factor for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 258 cases of invasive ductal carcinoma into those with and those without a fibrotic focus to investigate whether the presence of a fibrotic focus was significantly associated with the degree of tumor-associated macrophage (CD68, CD163 or CD204-positive) infiltration or whether the presence of tumor-associated macrophage infiltration heightened the malignant potential of invasive ductal carcinoma with a fibrotic focus. Multiple regression analyses demonstrated that a fibrotic focus was the only factor that was significantly associated with a high level of CD68-, CD163- or CD204-positive tumor-associated macrophage infiltration. The combined assessment of the presence or absence of a fibrotic focus and a high or a low level of CD204-positive tumor-associated macrophage infiltration clearly demonstrated that CD204-positive tumor-associated macrophage infiltration had a significant prognostic power only for patients with invasive ductal carcinoma with a fibrotic focus in multivariate analyses; CD204-positive tumor-associated macrophages might only exert a significant effect on tumor progression when a fibrotic focus is present within the invasive ductal carcinoma of the breast.

Perioperative nutrition management as an important component of surgical capacity in low- and middle-income countries.

Needs for surgical care are growing in low- and middle-income countries. Existing surgical care capacity indicators, focusing on the availability of equipment, personnel, and operation and anaesthetic skills, are not intended to evaluate perioperative nutrition management, which influences surgical outcomes. In this narrative review, we describe the prevalence of malnutrition and its clinical consequences among surgical patients in low- and middle-income countries, suggest potential measures to improve nutrition management and discuss the necessity of considering nutrition management as a component of surgical care capacity.

Neoadjuvant triweekly nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide for Stage II/III HER2-negative breast cancer: evaluation of efficacy and safety.

OBJECTIVE: Nanoparticle albumin-bound paclitaxel (nab-PTX) is a solvent-free paclitaxel coupled to human albumin without an associated increase in toxicity. The neoadjuvant study of primary breast cancer was planned to evaluate tumor response and safety of triweekly nanoparticle albumin-bound paclitaxel. METHODS: Patients with Stage II/III HER2-negative primary breast cancer received four courses of nanoparticle albumin-bound paclitaxel 260 mg/m(2) every 3 weeks (q3w), followed by four courses of epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) q3w. Tumor response after nanoparticle albumin-bound paclitaxel was histologically evaluated. In addition, the clinical response, breast-conserving rate and safety of this treatment were monitored. RESULTS: Among 53 patients who received nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide neoadjuvant chemotherapy, pathological complete response and near-pathological complete response were confirmed in 3 (5.7%) and 7 (13.2%) patients who had surgery, respectively. The overall objective response rate was 71.7% after completion of chemotherapy. Based on Positron Emission Tomography Response Criteria in Solid Tumors using (18)F-fluorodeoxyglucose, complete metabolic response and partial metabolic response after 2-3 courses of nanoparticle albumin-bound paclitaxel were 15.1 and 52.8%, respectively. The most common significant toxicities of q3w nanoparticle albumin-bound paclitaxel were Grade 3 muscle pain, neuropathy and febrile neutropenia, each in 1 (1.9%) patient. There were no incidences of anaphylaxis or Grade 4/5 adverse events. CONCLUSION: Neoadjuvant chemotherapy using q3w nanoparticle albumin-bound paclitaxel followed by epirubicin and cyclophosphamide was feasible in breast cancer patients with acceptable clinical response and drug tolerance, but conferred a low rate of pathological complete response. Monotherapy with q3w nanoparticle albumin-bound paclitaxel could be an appropriate substitute for solvent-based taxane in terms of therapeutic and safety management.

Grading system for blood vessel tumor emboli of invasive ductal carcinoma of the breast.

We previously reported that the number of mitotic and apoptotic figures in tumor cells in blood vessel tumor emboli had the greatest significant power for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. The purpose of the present study was to devise a grading system for blood vessel tumor emboli based on the mitotic and apoptotic figures of tumor cells in blood vessel tumor emboli, enabling accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 263 invasive ductal carcinomas into the following 3 grades according to the numbers of mitotic and apoptotic figures in tumor cells located in blood vessels within 1 high-power field: grade 0, no blood vessel invasion; grade 1, absence of mitotic figures and presence of any number of apoptotic figures, or 1 mitotic figure and 0 to 2 apoptotic figures; and grade 2, 1 mitotic figure and 3 or more apoptotic figures, or 2 or more mitotic figures and 1 or more apoptotic figures. Multivariate analyses with well-known prognostic factors demonstrated that grade 2 blood vessel tumor emboli significantly increased the hazard ratios for tumor recurrence independent of the nodal status, pathological TNM stage, hormone receptor status, or HER2 status. The presently reported grading system for blood vessel tumor emboli is the strongest histologic factor for accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast.

Safety and feasibility of adjuvant chemotherapy with S-1 in Japanese breast cancer patients after primary systemic chemotherapy: a feasibility study.

BACKGROUND: Advanced breast cancer patients have a higher risk of postoperative recurrence than early-stage breast cancer patients. Recurrence is believed to be caused by the increase in micrometases, which were not eradicated by preoperative or postoperative chemotherapy. Therefore, a new therapeutic strategy that can improve treatment efficacy is mandatory for advanced breast cancer. S-1 was shown to be effective and safe in Japanese metastatic breast cancer patients treated with previous chemotherapy, including anthracyclines. Thus, in this study, we evaluated S-1 as adjuvant chemotherapy in breast cancer patients after standard primary systemic chemotherapy. METHODS: The treatment consisted of 18 courses (a 2-week administration and a 1-week withdrawal; one year) administered at 80-120 mg/body/day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on Day 1 of the study. If the estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted, concurrently. RESULTS: Of the 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. Thirty-two of the 43 (74.4%) patients received concurrent radiotherapy. Twenty-two of the 43 (51.2%) patients completed the scheduled courses of chemotherapy. The most common reasons for withdrawal of treatment were subjective symptoms, such as nausea, anorexia, or general fatigue during the first 9 courses of treatment in 9/43 (20.9%) patients, recurrence in 7/43 (16.3%) patients, and adverse events in 5/43 (11.6%) patients. The cumulative percentage of administration for 365 days was 66.4% (95% confidence interval: 50.8-79.1%). Although grade 3 neutropenia (9.3%), leukopenia (4.7%), and diarrhea (4.7%) were observed, they were manageable. No grade 4 adverse effects were observed. CONCLUSIONS: The percentage of Japanese breast cancer patients completing the 18-course treatment and the cumulative percentage of administration for 365 days using S-1 after standard primary systemic chemotherapy were similar with the results of another study of adjuvant chemotherapy for the Japanese gastric cancer patients with no severe adverse effects. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan, and it is expected that S-1 will have a significant survival benefit in breast cancer patients. UMIN000013469.

[Successful treatment of trastuzumab-resistant HER2-positive breast cancer with extensive liver metastases using the combination of trastuzumab and capecitabine - a case report].

We report a case of a trastuzumab-resistant human epidermal growth factor receptor-2(HER2)-positive breast cancer patient with extensive liver metastases and associated impaired liver function, who showed an excellent response to the combination of trastuzumab and capecitabine. The patient was a 59-year-old postmenopausal woman with multiple liver metastases at first examination. She first received anthracycline-based chemotherapy, and after progression was followed up with a combination of trastuzumab and paclitaxel. Despite an initial response to this treatment, liver metastases rapidly progressed. Although palliative treatment was considered because of her impaired liver function, she received capecitabine while continuing trastuzumab. This combination therapy showed an excellent response, and a good quality of life(QOL)was maintained for a long time without any severe adverse events. The continuation of trastuzumab is considered effective after having progressed by trastuzumab including pretreatment, and we consider it worth while to give a combination of trastuzumab and capecitabine to patients with extensive liver metastases and associated impaired liver function, because of the treatment's synergistic effect and low risk of causing severe adverse events.

Axillary ultrasound examination is useful for selecting patients optimally suited for sentinel lymph node biopsy after primary systemic chemotherapy.

BACKGROUND: Controversy surrounds the reliability of sentinel lymph node biopsy after primary systemic chemotherapy. In this study, we assessed axillary ultrasound for selecting patients most likely to optimally benefit from biopsy. METHODS: The study included 87 patients who received primary systemic chemotherapy and underwent a sentinel lymph node biopsy followed by axillary lymph node dissection. Lymph nodes >10 mm in diameter, irregularly swollen, round, and homogeneously hypoechoic without an echo-rich center were considered axillary ultrasound positive. RESULTS: In axillary ultrasound-negative patients before and after primary systemic chemotherapy, identification, sensitivity, and false-negative rates were 81%, 100%, and 0%, respectively. However, in patients whose lymph nodes converted from positive to negative after primary systemic chemotherapy, these values were 83%, 70.8%, and 29.2%, respectively. CONCLUSIONS: Axillary ultrasound-negative patients before and after primary systemic chemotherapy were suitable for sentinel lymph node biopsy. Axillary ultrasound should be used during primary systemic chemotherapy and before surgery.

Role of the long form leptin receptor and of the STAT3 signaling pathway in colorectal cancer progression.

Although a number of recent studies have reported the involvement of leptin in colorectal carcinogenesis, findings are contradictory and difficult to interpret. Our group has previously reported that leptin signaling might have an important role in the development of colorectal adenomas. In this study, we investigated leptin signaling in colorectal carcino-genesis focusing in particular on the differences in leptin signaling between colorectal adenoma and cancer. Whereas no significant differences in the serum leptin levels were observed among normal control subjects and adenoma/cancer patients, increased expression and activation of the long form leptin receptor (ObRL) was observed in colorectal adenoma and cancer tissues compared with the normal colorectal tissues. However, no significant differences were observed between the colorectal adenoma and cancer tissues. Significant increases in the phosphorylation levels of important molecules of the JAK/STAT signaling pathway, located downstream of leptin signaling, and transcriptional regulation of STAT3-downstream target molecules were observed in colorectal adenoma tissue compared with the findings in normal colorectal tissues. Furthermore, these changes were significantly more pronounced in colorectal cancer compared to colorectal adenoma tissues. This is the first analysis of leptin and JAK/STAT signaling in a human colorectal adenoma-carcinoma sequence. These results suggest that the STAT3-mediated leptin signaling through the activation of ObRL may be involved in colorectal carcinogenesis, both in adenoma formation and in the progression to cancer. STAT3 signaling in colorectal cancer may be mediated not only by leptin but by other factors.

Leptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesis.

BACKGROUND AND AIMS: Obesity increases the risk of colorectal cancer (CRC). Serum leptin levels are markedly elevated in obese individuals, but the involvement of leptin in CRC growth remains unclear. We explored the hypothesis that leptin signalling regulates the growth of CRC, by examining the effects of leptin deficiency on murine colon tumour growth. METHODS: We used genetic (leptin-deficient and leptin receptor-deficient) models of obesity and investigated carcinogen-induced colon polyp formation and cell proliferation in the colonic epithelium. Colonic tissues and cell lines were analysed by histopathology and molecular-biology methods. RESULTS: A significant increase in the proliferative activity of normal colonic epithelial cells was observed in the obesity model; on the other hand, significant decrease of tumour cell proliferation was observed in leptin-deficient tumours, and tumour growth was dramatically inhibited in leptin-deficient and leptin-receptor-deficient mice despite the animals exhibiting severe obesity. Notably, a marked increase of the leptin receptor (ObR) expression levels was observed in colon tumours as compared to the normal epithelium. Nuclear ß-catenin staining was pronounced in all tumours, irrespective of leptin deficiency, whereas altered cellular localisation of ß-catenin was not observed in the normal colonic epithelial cells. In vitro, ß-catenin knockdown decreased ObR expression, and stimulation of recombinant Wnt increased ObR expression. In addition, the proliferative and survival effects of leptin were found to be mediated by the ObR/signal transducer and activator of transcription 3 (STAT3) signalling in colon tumours. CONCLUSIONS: Our findings indicate that leptin is important for CRC growth in obesity, and acts as a growth factor for CRC at stages subsequent to tumour initiation in colorectal carcinogenesis. Thus, inhibition of leptin signalling may be an effective strategy for therapy and prevention of colonic adenoma and cancer, which show activation of Wnt signalling.

Leptin receptor is involved in STAT3 activation in human colorectal adenoma.

The possible role of leptin in colorectal tumors has been investigated in previous studies; however, to date, the conclusions remain under debate. Therefore, we investigated the serum leptin levels in colorectal adenoma patients. In addition, expression of the leptin receptor, and the leptin receptor-mediated signaling pathways were investigated in biopsy specimens collected from human patients with colorectal adenoma. No significant difference in the mean serum leptin level was observed between the colorectal adenoma patients and the control subjects; however, increased expression and activation of the leptin receptor, as indicated by findings such as the phosphorylation of Tyr 1141, was observed in the colorectal adenoma tissues. In addition, activation of the JAK/STAT signaling pathway mediated by the leptin receptor and increased transcriptional regulation of downstream target molecules were observed in colorectal adenomas compared with the non-adenoma tissues. These results indicate STAT3-mediated leptin receptor signaling pathways may be activated in human colorectal adenomas.

Relationship between estrogen, vasomotor symptoms, and heart rate variability in climacteric women.

The present study investigated resting cardiac autonomic function in Japanese climacteric women using heart rate variability (HRV) power spectral analysis to evaluate the relationship between HRV indices and estrogen, as well as the ability of each HRV index to predict vasomotor symptoms. Forty-five peri- and postmenopausal women completed a questionnaire about the presence of vasomotor symptoms (hot flashes, sweating). To analyze the relationship between HRV and hot flashes or sweating, we classified subjects into groups based on symptoms and combinations of symptoms: no hot flashes (H1), hot flashes (H2), non-sweating (S1), sweating (S2), neither hot flashes nor sweating (V1), either hot flashes or sweating (V2), and both hot flashes and sweating (V3). Values for total power and the low-frequency component of HRV were significantly lower in the H2 group than in H1 (p < 0.05); values for total power and the high-frequency and low-frequency components of HRV were significantly lower in group S2 than S1 (p < 0.05); and values for total power and the high-frequency and low-frequency component of HRV were significantly lower in groups V2 and V3 compared to V1 (p < 0.05). Clinical diagnosis of climacterium relies upon subjective complaints of patients. Our findings suggest that HRV indices may help to evaluate vasomotor symptoms.

PPARgamma Ligand as a Promising Candidate for Colorectal Cancer Chemoprevention: A Pilot Study.

Activating synthetic ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), such as pioglitazone, are commonly used to treat persons with diabetes mellitus with improvement of insulin resistance. Several reports have clearly demonstrated that PPARgamma ligands could inhibit colorectal cancer cell growth and induce apoptosis. Meanwhile, aberrant crypt foci (ACF) have come to be established as a biomarker of the risk of CRC in azoxymethane-treated mice and rats. In humans, ACF can be detected using magnifying colonoscopy. Previously, CRC and adenoma were used as a target for chemopreventive agents, but it needs a long time to evaluate, however, ACF can be a surrogate marker of CRC even for a brief period. In this clinical study, we investigated the chemopreventive effect of pioglitazone on the development of human ACF as a surrogate marker of CRC. Twenty-nine patients were divided into two groups, 20 were in the endoscopically normal control group and 9 were in the pioglitazone (15 mg/day) group, and ACF and adenoma were examined before and after 1-month treatment. The number of ACF was significantly decreased (5.8 +/- 1.1 to 3.3 +/- 2.3) after 1 month of pioglitazone treatment, however, there was no significant change in the number of crypts/ACF or in the number and size of adenomas. Pioglitazone may have a clinical application as a cancer-preventive drug. This investigation is just a pilot study, therefore, further clinical studies are needed to show that the PPARgamma ligand may be a promising candidate as a chemopreventive agent for colorectal carcinogenesis.

Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial.

The biguanide metformin is widely used for treating diabetes mellitus. We previously showed the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effect of metformin on rectal aberrant crypt foci (ACF), which are an endoscopic surrogate marker of colorectal cancer. We prospectively randomized 26 nondiabetic patients with ACF to treatment with metformin (250 mg/d, n = 12) or no treatment (control, n = 14); 23 patients were evaluable for end point analyses (9 metformin and 14 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory end point analyses). We also examined proliferative activity in colonic epithelium (via proliferating cell nuclear antigen labeling index) and apoptotic activity (via terminal deoxynucleotidyl transferase dUTP nick-end labeling). At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 +/- 6.45 before treatment versus 5.11 +/- 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 +/- 6.65 versus 7.56 +/- 6.75, P = 0.609). The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer.

Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase.

Metformin is widely used for the treatment of diabetes mellitus. Adenosine monophosphate-activated protein kinase (AMPK) is known to be activated by metformin and to inhibit the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the protein translational machinery and cell proliferation. We examined the effect of metformin on the suppression of colorectal carcinogenesis in chemical carcinogen-induced models. Seven-wk-old BALB/c mice were intraperitoneally (i.p.) injected with azoxymethane (AOM, 10 mg/kg) and then treated with or without metformin (250 mg/kg/d) for 6 wk (for the investigation of aberrant crypt foci [ACF] formation) or 32 wk (for polyp formation). We next investigated colonic epithelial proliferation using bromodeoxyuridine (BrdU) and the proliferating cell nuclear antigen (PCNA) labeling indices. Furthermore, to examine the indirect effect of metformin, the insulin resistance status and the serum lipid levels were assessed. Treatment with metformin significantly reduced ACF formation. The effect of metformin on colon polyp inhibition was relatively modest. No significant difference in body weight or glucose concentration was observed. The BrdU and PCNA indices decreased in mice treated with metformin. A Western blot analysis revealed that the phosphorylated mTOR, S6 kinase, and S6 protein levels in the colonic mucosa decreased significantly in mice treated with metformin. In conclusion, metformin suppresses colonic epithelial proliferation via the inhibition of the mTOR pathway through the activation of AMPK. As metformin is already used daily as an antidiabetic drug, it might be a safe and promising candidate for the chemoprevention of colorectal cancer.

Adiponectin inhibits colorectal cancer cell growth through the AMPK/mTOR pathway.

Adiponectin is a peptide hormone secreted by adipose tissue. It is a key hormone responsible for insulin sensitization, and its circulating level is inversely associated with abdominal obesity. Recent studies have shown that a reduced plasma adiponectin level is significantly correlated with the risk of various cancers. However, there are few studies regarding the association of adiponectin and colorectal cancer. To address this issue, we investigated the effect of adiponectin on colorectal cancer cells. Three colorectal cancer cell lines express both AdipoR1 and AdipoR2 receptors. MTT assay revealed that adiponectin inhibited human colorectal cancer cell growth. Furthermore, Western blot analysis revealed that adiponectin activated adenosine monophosphate-activated protein kinase (AMPK) and suppressed mammalian target of rapamycin (mTOR) pathways. Selective AMPK inhibitor compound C abrogated the inhibitory effect of adiponectin on cell growth. Our results clearly demonstrate the novel findings that adiponectin inhibits colorectal cancer cell growth via activation of AMPK, thereby down-regulating the mTOR pathway.

Association of visceral fat accumulation and plasma adiponectin with rectal dysplastic aberrant crypt foci in a clinical population.

The association between obesity and the risk of colorectal cancer (CRC) cannot be easily evaluated because CRC itself is associated with a gradual loss of bodyweight. Aberrant crypt foci (ACF) can be classified as dysplastic ACF or non-dysplastic ACF by magnifying colonoscopy, and dysplastic ACF are thought to be a biomarker of CRC. Ninety-four participants who underwent colonoscopy at Yokohama City University Hospital, Japan, were enrolled in the current study. We detected 557 ACF, including 67 dysplastic ACF (12.0%). Univariate regression analysis was conducted to determine correlations between the number of dysplastic ACF and various potential risk factors, including patient age, waist circumference, body mass index, visceral fat area (VFA), and plasma adiponectin level. The results of multiple regression analysis revealed that the number of dysplastic ACF correlated with age (correlation coefficient r=0.212, P=0.0383) and plasma adiponectin level (r=-0.201, P=0.0371), even after adjustments for sex, waist circumference, body mass index, and VFA. Our univariate correlation analysis data showed a significant correlation with the number of dysplastic ACF with VFA (r=0.238, P=0.0209), no correlation with subcutaneous fat area, and an inverse correlation with the plasma level of adiponectin (r=-0.258, P=0.0118). Thus, our results suggest that aging and visceral fat accumulation could correlate moderately with colorectal carcinogenesis. The novelty of our study lies in the finding that visceral fat accumulation and a low plasma adiponectin level may promote colorectal carcinogenesis; therefore, these obesity-related parameters may serve as novel targets for CRC prevention.

Inhibition of peroxisome proliferator-activated receptor gamma promotes tumorigenesis through activation of the beta-catenin / T cell factor (TCF) pathway in the mouse intestine.

Although peroxisome proliferator-activated receptor gamma (PPARgamma) is strongly expressed in the intestinal epithelium, the role of PPARgamma in intestinal tumorigenesis has not yet been elucidated. To address this issue, we investigated the effect of PPARgamma inhibition and its mechanism on intestinal tumorigenesis using a selective antagonist, T0070907. We treated Apc(Min/+) mice and carcinogen-induced colon cancer model C57BL/6 mice with T0070907 and counted the number of spontaneous polyps and aberrant crypt foci and observed cell proliferation and beta-catenin protein in the colon epithelium. To investigate its mechanism, the changes of beta-catenin/TCF (T cell factor) transcriptional activity and location of beta-catenin induced by T0070907 were investigated in the colon cancer cell lines. T0070907 promoted polyp formation in the small intestine of Apc(Min/+) mice and aberrant crypt foci in the colon of C57BL/6 mice. PPARgamma inhibition promoted cell proliferation and increased expressions of the c-myc and cyclin D1 genes and the beta-catenin protein in the colon epithelium. In vitro, cell proliferation was promoted, but it was inhibited by the transfection of dominant-negative Tcf4. T0070907 increased beta-catenin/TCF transcriptional activity and beta-catenin protein in the cytsol and nucleus, but relatively decreased it on the cell membrane. PPARgamma antagonist promotes tumorigenesis in the small intestine and colon through stimulation of epithelial cell proliferation. beta-Catenin contributes to the promotion of tumorigenesis by PPARgamma antagonist due to activation of TCF/LEF (lymphoid enhancer factor) transcriptional factor.

Inhibition of peroxisome proliferator-activated receptor gamma activity suppresses pancreatic cancer cell motility.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that has been implicated in the carcinogenesis and progression of various solid tumors, including pancreatic carcinomas. We aimed to clarify the role of this receptor in pancreatic cell motility in vitro and in metastasis in vivo. Cell motility was examined by assaying transwell migration and wound filling in Capan-1 and Panc-1 pancreatic cancer cells, with or without the PPARgamma-specific inhibitor T0070907. A severe combined immunodeficiency xenograft metastasis model was used to examine the in vivo effect of PPARgamma inhibition on pancreatic cancer metastasis. In both transwell-migration and wound-filling assays, inhibition of PPARgamma activity suppressed pancreatic cell motility without affecting in vitro cell proliferation. Inhibition of PPARgamma also suppressed liver metastasis in vivo in metastatic mice. In PPARgamma-inhibited cells, p120 catenin accumulation was induced predominantly in cell membranes, and the Ras-homologous GTPases Rac1 and Cdc42 were inactive. Inhibition of PPARgamma in pancreatic cancer cells decreased cell motility by altering p120ctn localization and by suppressing the activity of the Ras-homologous GTPases Rac1 and Cdc42. Based on these findings, PPARgamma could function as a novel target for the therapeutic control of cancer cell invasion or metastasis.