MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis.

Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidence have shown that microRNAs (miRs) can have an important role in cancer metastasis. Using isogenic pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149 to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G-protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of focal adhesion kinase and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and α5ß1 integrin via proteasome and lysosome pathways, respectively. Moreover, we found that GIT1 depletion in metastatic breast cancer cells greatly reduced α5ß1-integrin-mediated cell adhesion to fibronectin and collagen. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer, as well as with lymph node metastasis. We conclude that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149-GIT1 pathway in clinical diagnosis and therapeutics.

Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway.

Gain of function of membrane receptor was a good strategy exploited by cancer cells to benefit own growth and survival. Overexpression of HER2 has been found to serve as a target for developing trastuzumab to treat 20-25% of breast cancer. However, little or none of the other membrane receptor was found to be useful as a potential target for breast cancer treatment since then. Here, we showed that amplified signaling of interleukin-17 receptor B (IL-17RB) and its ligand IL-17B promoted tumorigenicity in breast cancer cells and impeded acinus formation in immortalized normal mammary epithelial cells. External signal transmitted through IL-17RB activated nuclear factor-κB to upregulate antiapoptotic factor Bcl-2 and induced etoposide resistance. Elevated expression of IL-17RB had a stronger correlation with poor prognosis than HER2 in breast cancer patients. Interestingly, breast cancer patients with high expression of IL-17RB and HER2 had the shortest survival rate. Depletion of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumorigenic activity, suggesting that IL-17RB and HER2 have an independent role in breast carcinogenesis. Furthermore, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells. These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.

Association of metabolic syndrome, atherosclerosis risk factors, sex hormones in ED in aboriginal Taiwanese.

The overall prevalence of metabolic syndrome (MS) in aboriginal male Taiwanese is very high. Many studies have found that those with cardiovascular disease and MS have a significantly higher risk of ED. In this study, we attempted to find the correlation among MS risk factor, atherosclerosis risk factors and low serum testosterone in relation to the development of ED. This was a cross-sectional study of 238 cases, and collected data included demographic data, lifestyle questionnaires, sexual desire scale, sexual satisfaction scale and International Index of Erectile Function (IIEF) questionnaire. Among our 238 subjects, 146 had MS (61.3%) and 114 subjects with MS had ED (85.7%). Using age-adjusted multivariate logistic regressive analysis, this study showed that aboriginal males with ED had a significantly higher prevalence of MS (OR=12.02, 95% confidence intervals (CI): 6.33-22.83, P<0.001). Among the MS components, abnormal fasting blood sugar was the most significantly independent factor for ED in aboriginal males (OR=8.94, 95% CI: 4.71-16.97, P<0.001). The presence of MS had a significant correlation with lower IIEF-5 scores, lower sexual desire scores, lower testosterone serum level (P<0.01) and abnormal interleukin-6 (IL-6) and high sensitivity C-reactive protein (HsCRP). The results of this study support the idea that MS, low serum testosterone and HsCRP may predict ED in aboriginal Taiwanese males. Further studies with population-based and longitudinal design should be conducted to confirm this finding and design to compare rates of ED in aboriginal men with MS.

Lack of efficacy to systemic chemotherapy for treatment of metaplastic carcinoma of the breast in the modern era.

Metaplastic carcinoma of the breast (MCB) is a rare subtype of breast cancer. Anecdotal reports are available regarding its response to systemic chemotherapy. We reviewed the records of patients diagnosed with MCB at National Taiwan University Hospital between 1988 and 2009. A total of 46 MCB cases were identified from 8,695 breast tumor patients who underwent biopsy or resection. About 11 of 25 patients with initial bulky disease (T3-4) received neoadjuvant chemotherapy before surgery, and 2 (18.2%) exhibited a partial response. About 12 of 18 patients who developed distant metastasis received palliative systemic chemotherapy. Of them, only 1 (8.3%), 1 (10%), and none (0%) responded to first-, second-, or third- and beyond line chemotherapy, respectively. None of the patients who received anthracyline- (n = 13), vinorelbine- (n = 7), or cyclophosphamide-based (n = 18) chemotherapy responded, whereas 3 (17.6%) of 17 patients who received taxane-based chemotherapy exhibited a partial response. Tumor response to systemic chemotherapy remains generally poor for MCB patients. Taxanes may have modest activity, but need to be validated in further studies.

miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1.

MicroRNAs (miRNAs) are involved in tumorigenecity by regulating specific oncogenes and tumor suppressor genes, and their roles in breast cancer stem cells (BCSCs) are becoming apparent. Distinct from the CD44(+)/CD24(-/low) sub-population, we have isolated a novel PROCR(+)/ESA(+) BCSC sub-population. To explore miRNA-regulatory mechanisms in this sub-population, we performed miRNA expression profiling and found miR-495 as the most highly upegulated miRNA in PROCR(+)/ESA(+) cells. Coincidently, high upregulation of miR-495 was also found in CD44(+)/CD24(-/low) BCSCs, reflecting its potential importance in maintaining common BCSC properties. Ectopic expression of miR-495 in breast cancer cells promoted their colony formation in vitro and tumorigenesis in mice. miR-495 directly suppressed E-cadherin expression to promote cell invasion and inhibited REDD1 expression to enhance cell proliferation in hypoxia through post-transcriptional mechanism. miR-495 expression was directly modulated by transcription factor E12/E47, which itself is highly expressed in BCSCs. These findings reveal a novel regulatory pathway centered on miR-495 that contributes to BCSC properties and hypoxia resistance.

Cumulative survival in early-onset unilateral and bilateral breast cancer: an analysis of 1907 Taiwanese women.

As the epidemiological pattern of breast cancer in modernising Asian countries differs greatly from that in Western countries, it is worthwhile to investigate the long-term prognoses of unilateral and bilateral breast cancer in these nations. A retrospective cohort study composed of 1907 Taiwanese women was conducted to follow 1863 unilateral and 44 bilateral cases of breast cancer. Time-dependent Cox regression was used to assess the risk of breast cancer death by considering the time course of unilateral and bilateral tumour development. The 15-year survival rates were 68.37, 62.63, and 26.42% for unilateral, synchronous bilateral, and metachronous bilateral breast cancer, respectively. Differences among types were most apparent after 5 years of follow-up. After adjusting for significant prognostic factors, the risk of death for overall bilateral breast cancer was 2.50-fold greater (95% CI, 1.43-4.37) compared to unilateral breast cancer. The corresponding figures were 1.12-fold (95% CI, 0.42-3.02) and 6.11-fold (95% CI, 3.14-11.89) for synchronous and metachronous bilateral breast cancer, respectively. Taiwanese women, who are frequently diagnosed with breast cancer before 50 years of age, showed poorer survival for metachronous bilateral than for synchronous bilateral or unilateral breast cancer. Survival was markedly poorer compared to recent data from Sweden.

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial-mesenchymal transition.

Metaplastic carcinoma of the breast (MCB) is a poorly understood subtype of breast cancer. It is generally characterized by the coexistence of ductal carcinomatous and transdifferentiated sarcomatous components, but the underlying molecular alterations, possibly related to epithelial-mesenchymal transition (EMT), remain elusive. We performed transcriptional profiling using half-a-genome oligonucleotide microarrays to elucidate genetic profiles of MCBs and their differences to those of ductal carcinoma of breasts (DCBs) using discarded specimens of four MCBs and 34 DCBs. Unsupervised clustering disclosed distinctive expression profiles between MCBs and DCBs. Supervised analysis identified gene signatures discriminating MCBs from DCBs and between MCB subclasses. Notably, many of the discriminator genes were associated with downregulation of epithelial phenotypes and with synthesis, remodeling and adhesion of extracellular matrix, with some of them have known or inferred roles related to EMT. Importantly, several of the discriminator genes were upregulated in a mutant Snail-transfected MCF7 cell known to exhibit features of EMT, thereby indicating a crucial role for EMT in the pathogenesis of MCBs. Finally, the identification of SPARC and vimentin as poor prognostic factors reinforced the role of EMT in cancer progression. These data advance our understanding of MCB and offer clues to the molecular alterations underlying EMT.

Biological functions of the ING family tumor suppressors.

Early studies of the inhibitor of growth 1 ( ING1) gene, the founding member of the ING tumor suppressor family, demonstrated that this gene plays an important role in apoptosis and cellular senescence. Four other related genes have since been identified and found to be involved in various biological activities, including cell cycle arrest, regulation of gene transcription, DNA repair and apoptosis. The biochemical functions of ING proteins as histone acetyltransferases and histone deacetylase co-factors ties this new tumor suppressor family to the regulation of transcription, cell cycle check-points, DNA repair and apoptosis. This review is aimed at summarizing the known biological functions of the ING tumor suppressors and the signalling pathways that they involve.

Significant differences in serum activities of matrix metalloproteinase-2 and -9 between HCV- and HBV-infected patients and carriers.

To examine the possible involvement of MMP-9 and -2 in the development of liver diseases caused by HCV or HBV infection, serum activities of both enzymes were studied by zymograph. Eight groups of subjects (60 for each) were examined in the study: healthy control, patients with hepatoma, liver cirrhosis, chronic hepatitis B or chronic hepatitis C, and carriers positive for HBsAg, both HBsAg and HBeAg, or anti-HCV. The results showed significant changes in the MMP-9 and -2 activities in the carriers. The presence of HBeAg was accompanied by a highest activity of MMP-2 and an inversely correlated (r=-0.578, P=<0.001), lowest activity of MMP-9 among all groups. For those with active liver diseases, MMPs activities were fluctuated at each stage of pathological symptoms. Chronic hepatitis B and C patients had significant different serum MMP-2 and -9 activities. These findings imply an influence on the balance of MMPs system by the existence of virus that might influence the following progression of liver disease, and a distinction between the pathological mechanisms of HCV and HBV. Since the serum MMPs activities were significantly varied between each stage of liver disease, an individual profile of these parameters might serve as an easy accessing serum marker to monitor the progression of liver disease.

Endoscopic cryotherapy: experimental results and first clinical use.

BACKGROUND: Cryotherapy or the application of extreme cold has many potential applications in gastroenterology including tissue destruction and hemostasis but until now its development has been prevented by the lack of a delivery device suitable for use through the endoscope. We report here our experience with prototype devices using both liquid nitrogen driven by a cryosurgical system and cryogenic refrigerants (nitrous oxide and carbon dioxide) at or near ambient temperature. METHODS: Cryotherapy was applied to the distal esophageal mucosa of dogs via a flexible catheter passed through an upper endoscope. In other dogs, cryotherapy was used for hemostasis in a bleeding ulcer model. The procedure was also used for palliation in a 58-year-old man with unresectable adenocarcinoma of the stomach with pyloric channel obstruction. RESULTS: Freezing of the superficial mucosa was nearly instantaneous. All dogs survived the procedure and appeared to thrive. Histologic evaluation revealed significant necrosis of the superficial epithelial layer accompanied by a fibrinocellular infiltrate on the surface. These markers of acute injury subside by the fourth to sixth day and are replaced by regenerating epithelium, a process that is virtually complete by day 10. In the hemostasis experiments, bleeding ceased immediately after cryospraying of the lesions but resumed on thawing in most cases. Application of cryotherapy in the patient resulted in reduction of the pyloric mass with no immediately apparent adverse effects. CONCLUSIONS: These data, although preliminary, demonstrate the feasibility of endoscopic cryotherapy using a simple hand-held device. This device has broad potential for use in gastroenterology including ablation of superficial epithelium, debulking of large tumors and hemostasis.

Reflux strictures of the esophagus.

Gastroesophageal reflux disease (GERD) is the most common cause of esophageal strictures, accounting for approximately 70% of all cases. Reflux strictures of the esophagus are serious complications of GERD and are associated with a high relapse rate. Goals of long-term management include the relief of dysphagia, prevention of stricture recurrence, and avoidance of complications with safe, cost-effective therapy. Despite recent advances in knowledge about GERD, reflux stricture still remains a relatively common and challenging clinical problem.

Laparoscopic subtotal gastrectomy with lymphadenectomy in a patient with early gastric cancer.

Laparoscopic surgery is rapidly gaining in popularity among general surgeons. It is not widely used to treat abdominal malignancies because of technical difficulties and the fear of peritoneal dissemination. We describe the use of laparoscopic surgery to treat early gastric cancer. A 66-year-old man was diagnosed with early gastric adenocarcinoma by endoscopic ultrasonography and biopsy. Subtotal gastrectomy along with removal of the perigastric (D1) and selective extraperigastric lymph nodes over the celiac trunk was accomplished laparoscopically, through five punctures and a minilaparotomy. The patient's convalescence was uneventful. Bowel sounds were heard on postoperative day 1. On postoperative day 3, he passed flatus. The patient was started on a clear liquid diet on postoperative day 5. There was neither leakage nor obstruction after oral intake. He was discharged on postoperative day 11. No local recurrence or distant metastasis was found during 16 months' follow-up. This is the first report of successful laparoscopic resection of early gastric cancer with lymph node dissection in Taiwan.

The role of sphincter of Oddi manometry in the diagnosis and therapy of pancreatic disease.

Endoscopic manometry of the sphincter of Oddi (SO) is now an accepted technique in the diagnosis and therapy of biliary disease. Its role in the evaluation of pancreatic sphincter function for pancreatic diseases, however, is evolving. There are now preliminary data to suggest that pancreatic SO manometry may identify a subgroup of patients with pancreatic sphincter dysfunction that may benefit from endoscopic therapy. Further prospective clinical trials are sorely needed to evaluate the response of endoscopic therapy based on pancreatic SO basal pressure or pancreatic ductal pressure.