Seryl-tRNA synthetase promotes translational readthrough by mRNA binding and involvement of the selenocysteine incorporation machinery.

Translational readthrough of UGA stop codons by selenocysteine-specific tRNA (tRNASec) enables the synthesis of selenoproteins. Seryl-tRNA synthetase (SerRS) charges tRNASec with serine, which is modified into selenocysteine and delivered to the ribosome by a designated elongation factor (eEFSec in eukaryotes). Here we found that components of the human selenocysteine incorporation machinery (SerRS, tRNASec, and eEFSec) also increased translational readthrough of non-selenocysteine genes, including VEGFA, to create C-terminally extended isoforms. SerRS recognizes target mRNAs through a stem-loop structure that resembles the variable loop of its cognate tRNAs. This function of SerRS depends on both its enzymatic activity and a vertebrate-specific domain. Through eCLIP-seq, we identified additional SerRS-interacting mRNAs as potential readthrough genes. Moreover, SerRS overexpression was sufficient to reverse premature termination caused by a pathogenic nonsense mutation. Our findings expand the repertoire of selenoprotein biosynthesis machinery and suggest an avenue for therapeutic targeting of nonsense mutations using endogenous factors.

EPS8 regulates an NLRP3 inflammasome-independent caspase-1 activation pathway in monosodium urate crystal-treated RAW264.7 macrophages.

Gout is an inflammatory arthritis caused by the phagocytosis of monosodium urate (MSU) crystal deposition in joints. NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome-dependent caspase-1 activation is implicated in the processing of interleukin-1ß (IL-1ß), which is the major effector cytokine in the acute inflammatory response of gout. Mechanisms underlying caspase-1 activation remain unclear. Epidermal growth factor receptor pathway substrate no. 8 (Eps8) is a signal transducer and actin filament organizer that plays a key role in lipopolysaccharide-stimulated phagocytosis in macrophages. Here, RAW264.7 macrophages that have no intact NLRP3 inflammasomes were used to investigate the role of Eps8 in MSU crystal-mediated caspase-1 activation. A kinetic study revealed that the induction of Eps8 expression by MSU crystals occurred before NLRP3, p46/p33 caspase-1, and mature IL-1ß in RAW 264.7 cells. In addition, actin cytoskeleton dynamics was required for Eps8 induction and caspase-1 activation in MSU crystal stimulation. Silencing Eps8 had no effect on the basal expression of p46/p33 caspase-1 and NLRP3, but nearly abolished MSU crystal-induced NLRP3 expression and caspase-1 activation. Furthermore, MSU crystals induced Eps8-pro-caspase-1 complex formation and Eps8 formed a stable complex with p33 caspase-1, but not with NLRP3. In summary, our results demonstrated for the first time the importance of Eps8 in MSU crystal-mediated caspase-1 activation without the involvement of NLRP3 inflammasomes.

A Population-Based Study of Secondary Prostate Cancer Risk after Radiotherapy in Male Patients with Rectal Cancer: A Retrospective Cohort Study.

Background and objective: Risk of secondary prostate cancer after radiation therapy among patients with rectal cancer remains undetermined. Given an increased incidence of rectal cancer in younger people and improved survival for rectal cancer patients who received radiation therapy, the potential risk of secondary prostate cancer needs to be further investigated. Materials and Methods: Male patients (n = 11,367) newly diagnosed rectal cancer and who underwent abdominoperineal resection (APR) or low anterior resection (LAR) from 1 January, 1998 to 31 December, 2010 were identified from Taiwan National Health Insurance Research Database. The incidence and relative risk of secondary prostate cancer in study patients with (n = 1586) and without (n = 9781) radiotherapy within one year after rectal cancer diagnosis were compared using a competing-risks analysis. Results: Rectal cancer patients with radiotherapy were at a significantly decreased risk of developing prostate cancer, with a hazard ratio (HR) of 0.41 (95% confidence interval = 0.20⁻0.83) after adjustment for age. Analysis of the risk estimated for various follow-up lengths suggested that a decreasing HR was seen through the period followed-up and that there was a trend of decreasing prostate cancer risk with time after radiotherapy. Conclusions: Radiotherapy was significantly associated with decreased risk of secondary prostate cancer among rectal cancer patients, by a magnitude of 59%.

Mesh migration into the sigmoid colon mimics a colon tumor, a rare complication after herniorrhaphy: case report.

INTRODUCTION: Tension-free mesh repair is a widely used hernioplasty technique. However, mesh migration is a severe complication that may induce colon inflammation or perforation and can occur several months to several years following hernioplasty. CASE REPORT: We present a case where mesh migrated into the sigmoid colon 12 years postoperation and was mistaken for a colon tumor.

Secondary Cancers After Radiation Therapy for Primary Prostate or Rectal Cancer.

Literature about the risk of secondary cancer after radiation therapy (RT) of prostate and rectal cancer reveals contradictory results. We conducted a meta-analysis to examine whether the RT induces secondary rectal or prostate cancer in patients, respectively, with prostate or rectal cancer. All studies published in Medline or Pubmed up to March 3, 2015, containing RT of primary rectal or prostate cancer, and providing risk estimates of secondary prostate or rectal cancer were considered as eligible. Relative risk (RR) and standardized incidence ratios (SIR) were calculated using the random-effects model. Twenty studies met the inclusion criteria. 12 of them were from the Surveillance, Epidemiology, and End Results (SEER) database. For prostate cancer patients, pooled adjusted RRs or SIRs did not show an effect on the risk of secondary rectal cancer. However, notwithstanding the limitations of SEER-based studies, the subgroup of prostate cancer patients receiving external beam radiation therapy (EBRT) showed an increased risk of rectal cancer. For rectal cancer patients, pooled adjusted RR of prostate cancer was 1.12 (95 % CI, 0.44-2.8) and SIR was 0.40 (95 % CI, 0.29-0.55). All studies included in the SIR analysis of rectal cancer were derived from the SEER data source. Based on current evidence, RT for prostate cancer patients had no effect on rectal cancer incidence, except for patients who received EBRT therapy. However, compared with the general population, RT for rectal cancer is associated with a decreased prostate cancer risk as found in SEER-based studies.

Cost effectiveness of cancer treatment in Taiwan.

BACKGROUND/PURPOSE: This study aims to examine the cost effectiveness of treating major cancers compared with other major illnesses in Taiwan. METHODS: We collected data on 395,330 patients with cancer, 125,277 patients with end-stage renal disease, and 50,481 patients under prolonged mechanical ventilation during 1998-2007. They were followed for 10-13 years to estimate lifetime survival functions using a semiparametric method. EuroQol five-dimension was used to measure the quality of life for 6189 cancer patients and 1401 patients with other illnesses. The mean utility values and healthcare costs reimbursed by the National Health Insurance were multiplied with the corresponding survival probabilities to estimate quality-adjusted life expectancies and lifetime costs, respectively. Data of 22,344 cancer patients under hospice care (considered as a comparison group) were used to conduct a cost-effectiveness analysis. Sensitivity analysis was conducted by assuming patients without treatment survived for 2 years with a quality of life value of 0.5. RESULTS: The costs of care for patients under prolonged mechanical ventilation and those with end-stage renal disease were US$41,780-53,708 per quality-adjusted life year (QALY) and US$18,222-18,465 per QALY, respectively, which are equivalent to 2.17-2.79 gross domestic product (GDP) per capita per QALY and 1.18-1.25 GDP per capita per QALY. The costs of care for the nine different cancers were less than 1 GDP per capita per QALY, with those of lung, esophagus, and liver cancers being the highest. Sensitivity analysis showed the same conclusion. Lifetime risks of six out of nine cancer sites show an increased trend. CONCLUSION: Cancer care in Taiwan seemed cost effective compared with that of other illnesses, but prevention is necessary to make the National Health Insurance more sustainable.

SUMOylated CPAP is required for IKK-mediated NF-κB activation and enhances HBx-induced NF-κB signaling in HCC.

BACKGROUND & AIMS: Constitutive activation of NF-κB is an important event involved in chronic inflammation in hepatocellular carcinoma (HCC). CPAP, which plays important roles in centrosomal functions, was previously identified as the transcriptional co-activator of NF-κB. However, the molecular mechanism is unclear. The goal of this study was to investigate the role of CPAP in activating the NF-κB pathway in HCC. METHODS: SK-Hep1, HuH7, HepG2, HepG2X, Hep3B, and Hep3BX cells with CPAP overexpression or CPAP siRNA were used to evaluate activation of NF-κB under TNF-α stimulation by reporter assay, RT-PCR, Q-PCR, and Western blot analysis. In vivo SUMO modification of CPAP was demonstrated by an in situ PLA assay. Human HCC tissues were used to perform Q-PCR, Western blot, and IHC. RESULTS: CPAP siRNA abolished the interaction between IKKß and NF-κB, whereas overexpression of CPAP enhanced this interaction and finally led to augmented NF-κB activation by increasing the phosphorylation of NF-κB. CPAP could enter nuclei by associating with NF-κB. Furthermore, CPAP was SUMO-1 modified upon TNF-α stimulus, and this is essential for its NF-κB co-activator activity. SUMO-1-deficient CPAP mutant lost its NF-κB co-activator activity and failed to enter nuclei. Importantly, SUMOylated CPAP could synergistically increase the HBx-induced NF-κB activity. CONCLUSIONS: CPAP is essential for the recruitment of the IKK complex to inactivated NF-κB upon TNF-α treatment. Expression of CPAP was positively correlated with a poor prognosis in HBV-HCC. CPAP has the potential to serve as a therapeutic target for inflammation and inflammation-related diseases.

Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer.

The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and is associated with tumor malignancy. Pyruvate dehydrogenase kinase-1 (PDK1) and PDK3 participate in the metabolic switch of cancer cells; however, the medical significance of PDK1 and PDK3 in cancer progression is not known. Here, we assessed the expression profiles of PDK1 and PDK3 in colorectal cancer. Western blot analysis (n = 74) demonstrated that PDK3 was markedly increased in colon cancer compared to that in adjacent normal tissues, whereas PDK1 was decreased in cancer cells. In addition, PDK3 expression was positively correlated with that of hypoxia inducible factor-1α (HIF-1α) in cancer cells. Further analysis using immunohistochemical staining revealed that PDK3 levels were positively associated with severity of cancer and negatively associated with disease-free survival. In vitro studies using several colon cancer cell lines showed that PDK3 expression was controlled by HIF-1α and contributed to hypoxia-induced increased drug resistance, perhaps explaining why patients with PDK3 overexpression have a greater incidence of treatment failure. Taken together, our findings suggest that PDK3 plays an important role in the metabolic switch and drug resistance of colon cancer and is potentially a novel target for cancer therapy.

Aberrantly expressed AURKC enhances the transformation and tumourigenicity of epithelial cells.

Over-expression of AURKC has been detected in human colorectal cancers, thyroid carcinoma and several cancer cell lines. However, the regulation and clinical implications of over-expressed AURKC in cancer cells are unclear. Here we show that elevated AURKC increases the proliferation, transformation and migration of cancer cells. Importantly, the kinase activity of AURKC is required for these tumour-associated properties. Analysis of human cancer specimens shows that the expression of AURKC is increased in cervical cancer, and is highly correlated with staging in colorectal cancer. Over-expressed AURKC-GFP localizes to the centromeric regions of mitotic chromosomes and results in a decreased level of AURKB, a key regulator of spindle checkpoint. Expression of AURKC is down-regulated by PLZF, a transcriptional repressor, through recruitment to its promoter region. The expression levels of PLZF and AURKC mRNA display opposite patterns in human cervical and colorectal cancers. Taken together, our results provide important insights into human cancers with AURKC expression, which may serve as a potential target for cancer therapy in the future.

Computed tomography with histological correlation for evaluating tumor regression of rectal carcinoma after preoperative chemoradiation therapy.

BACKGROUND/AIMS: Preoperative chemoradiation therapy (CRT) is standard procedure for locally advanced rectal cancer. The correlation of tumor response evaluated using CT according to response evaluation criteria in solid tumors (RECIST) with the histo-logical tumor regression grade (TRG) is not well-documented. METHODOLOGY: Ninety-one patients with rectal cancer underwent CT examinations before and after preoperative CRT and following surgery. Clinical tumor staging and tumor response assessed according to RECIST were done on paired CT scans. Pathological tumor staging and TRGs were reviewed in resected specimens.Post-CRT CT findings and histological findings were compared. Survival analysis for 73 patients was done. RESULTS: TRG was positively correlated with the CT-assessed tumor response (r=0.276, p=0.009). Thickened fibrotic areas and muscle disarray caused by fibrosis were more frequently seen in cases of patients over-diagnosed as having residual tumors. The ycT status was positively correlated with ypT status (r=0.44, p<0.001;accuracy=61.5%). Downstaging of cT status was cor-related with a lower TRG (p=0.001). CONCLUSIONS: Fibrosis emerges after neoadjuvant therapy and is usual-ly accompanied by tumor reduction on CT scans of rec-tal cancer patients following preoperative CRT. There-fore, tumor response assessed using CT according to RECIST may serve as a supplementary tool for preoperative planning other than tumor restaging.

Dynamic change of tetraspanin CD151 membrane protein expression in colorectal cancer patients.

PURPOSE: To measure the CD151 expression in colorectal cancer (CRC). METHODS: CD151 expression was assessed in 179 CRC patients and 39 patients with hepatic liver metastasis. RESULTS: High CD151 expression was observed in 48% of patients with early-stage CRC versus only 33% of patients with metastatic colon cancer. A higher level of tumor invasion status correlated with a decrease in CD151 expression. Metastatic stage and advanced tumor stage correlated with a decreased CD151 expression. Twenty-seven out of the 39-paired samples had high CD151 expression in liver metastasis sites. CONCLUSIONS: CD151 expression is decreased in patients with metastatic CRC.

Rehabilitation exercise on the quality of life in anal sphincter-preserving surgery.

BACKGROUND/AIMS: In the recent years, there have been more and more patients with low rectal cancer who have received anal sphincter preserving surgery (ASPS). The defecation function greatly affects patient's postoperative social activity and quality of life. This study aimed to examine the effects of Kegel's exercise on postoperative anal defecation and quality of life of patients following sphincter preserving surgery. METHODOLOGY: A total of 34 patients received sphincter preserving surgery. 17 patients received instruction for Kegel's exercise postoperatively and 17 patients did not. Defecation function and quality of life were compared between the two groups by FACT-C questionnaire. RESULTS: The response rate of FACT-C questionnaire was 64.7% (22 in 34 patients). These 22 patients were divided into two groups: exercise group (n=11) and the non-exercise group (n=11). No significant differences were found in the demographic data between the two groups. Although the defecation frequency of the exercise group was better than the non-exercise group, no statistical difference was found. The total scores of the quality of life of the exercise group were significantly higher than those in the non-exercise group (p=0.038). CONCLUSIONS: This preliminary study found that Kegel's exercises may have a positive impact on the quality of life in patients undergoing anal sphincter preserving surgery.

Autophagy Upregulates miR-449a Expression to Suppress Progression of Colorectal Cancer.

Many studies reported that microRNAs (miRNAs) target autophagy-related genes to affect carcinogenesis, however, autophagy-deficiency-related miRNA dysfunction in cancer development remains poorly explored. During autophagic progression, we identified miR-449a as the most up-regulated miRNA. MiR-449a expression was low in the tumor parts of CRC patient specimens and inversely correlated with tumor stage and metastasis with the AUC (area under the curve) of 0.899 and 0.736 as well as poor overall survival rate, indicating that miR-449a has the potential to be a prognostic biomarker. In the same group of CRC specimens, low autophagic activity (low Beclin 1 expression and high p62 accumulation) was detected, which was significantly associated with miR-449a expression. Mechanistic studies disclosed that autophagy upregulates miR-449a expression through degradation of the coactivator p300 protein which acetylates the transcription factor Forkhead Box O1 (FoxO1). Unacetylated FoxO1 translocated to the nucleus and bound to the miR-449a promoter to drive gene expression. Either activation of autophagy by the inducer or overexpression of exogenous miR-449a decreases the expression of target gene LEF-1 and cyclin D1, which lead to decreased proliferation, colony formation, migration, and invasion of CRC cells. Autophagy-miR-449a-tartet genes mediated suppression of tumor formation was further confirmed in the xenograft mouse model. In conclusion, this study reveals a novel mechanism wherein autophagy utilizes miR-449a-LEF1-cyclin D1 axis to suppress CRC tumorigenesis. Our findings open a new avenue toward prognosis and treatment of CRC patients by manipulating autophagy-miR-449a axis.

Clinicopathological features of mismatch repair protein expression patterns in colorectal cancer.

Microsatellite instability (MSI) is reflective of a deficient mismatch repair (dMMR) system, which is mostly associated with the methylation of mismatch repair (MMR) genes and BRAF mutations in sporadic colorectal cancers (CRCs). We performed a retrospective study to analyze the clinicopathological features of dMMR CRCs and their association with the BRAF V600E mutation. The incidence of dMMR CRCs in our cohort was 7.4 % (118/1603). Immunohistochemistry (IHC) revealed four common dMMR IHC patterns in 116 dMMR CRCs from 110 patients. dMMR type 1 (MLH1-/PMS2-) CRCs were the most frequent pattern, usually showing typical proximal location and MSI histology. The BRAF V600E mutation was almost exclusively observed in dMMR type 1 (32 of 72) and dMMR type 2 (PMS- only, 7 of 18) CRCs (p = 0.001). Patients with dMMR type 3 (MSH2-/MSH6-) CRCs were usually diagnosed at younger ages (p < 0.001) and had the strongest family history of Lynch syndrome-associated tumors (p = 0.002). dMMR type 3 CRCs frequently presented at advanced stages (p = 0.005) with perineural invasion (p = 0.021). We also found a significant positive association of dMMR type 1 and type 3 with advanced stages of CRC, whereas dMMR types 2 and 4 (MSH6- only) were usually diagnosed at early stages of CRC (p < 0.001). In conclusion, BRAF V600E mutations almost exclusively occurred in dMMR type 1 and 2 CRCs. Patterns of MMR protein expression display distinct associations with tumor staging and age at diagnosis.

Pulmonary metastasectomy for colorectal cancer: Prognosis analysis disaggregated by the origin of the primary tumor.

BACKGROUND: The metastatic pattern differs between colon cancer and rectal cancer because of the distinct venous drainage systems. It is unclear whether colon cancer and rectal cancer are associated with different prognostic factors based on the anatomic difference. METHODS: We assessed the prognostic factors and survival outcomes of patients with colorectal cancer who underwent pulmonary metastasectomy (PM), disaggregated by the location of primary colorectal cancer. The Cox proportional hazards model was used to identify variables that influenced the outcomes of pulmonary metastasectomy. RESULTS: Between 2008 and 2017, 179 patients underwent PM classified into colon cancer and rectal cancer groups based on the site of origin of metastasis. The median postoperative follow-up was 2.3 years (range, 0.1-10.6). The post-PM 5-year survival rate in the colon cancer and rectal cancer groups was 42.5% and 39.9%, respectively (p = 0.310). On multivariable Cox proportional hazards analysis, presence of previous liver metastasis [hazard ratio (HR), 2.32; 95% confidence interval (CI), 1.19-4.51; p = 0.013], numbers of tumors (≥2; HR, 6.56; 95% CI, 2.07-20.79; p = 0.001), and abnormal preoperative carcinoembryonic antigen (CEA) level (HR, 2.50; 95% CI, 1.34-4.64; p = 0.001) were independent prognostic factors in patients with metastatic rectal cancer. CONCLUSIONS: Prognostic correlates of post-PM survival differ between colon and rectal cancer. Rectal cancer patients have worse prognosis if they have a history of liver metastasis, multiple pulmonary metastases, or abnormal preoperative CEA. These results may help assess the survival benefit of PM and facilitate treatment decision-making.

A selective Aurora-A 5'-UTR siRNA inhibits tumor growth and metastasis.

Many Aurora-A inhibitors have been developed for cancer therapy; however, the specificity and safety of Aurora-A inhibitors remain uncertain. The Aurora-A mRNA yields nine different 5'-UTR isoforms, which result from mRNA alternative splicing. Interestingly, we found that the exon 2-containing Aurora-A mRNA isoforms are predominantly expressed in cancer cell lines as well as human colorectal cancer tissues, making the Aurora-A mRNA exon 2 a promising treatment target in Aurora-A-overexpressing cancers. In this study, a selective siRNA, siRNA-2, which targets Aurora-A mRNA exon 2, was designed to translationally inhibit the expression of Aurora-A in cancer cells but not normal cells; locked nucleic acid (LNA)-modified siRNA-2 showed improved efficacy in inhibiting Aurora-A mRNA translation and tumor growth. Xenograft animal models combined with noninvasion in vivo imaging system (IVIS) analysis further confirmed the anticancer effect of LNA-siRNA-2 with improved efficiency and safety and reduced side effects. Mice orthotopically injected with colorectal cancer cells, LNA-siRNA-2 treatment not only inhibited the tumor growth but also blocked liver and lung metastasis. The results of our study suggest that LNA-siRNA-2 has the potential to be a novel therapeutic agent for cancer treatment.

Formosanin C-induced apoptosis requires activation of caspase-2 and change of mitochondrial membrane potential.

Formosanin C is a pure compound isolated from Paris formosana Hayata (Liliaceae). The antitumor efficacy of formosanin C has been observed in cultured cells and animal systems. However, the molecular mechanisms of formosanin C remain unknown. The results of the present study indicate that formosanin C induced apoptosis of HT-29 cells characterized by exposure of phosphatidylserine, accumulation of cells at the sub-G(1) phase, fragmentation of DNA, and change of nuclear morphology in a time- and dose-related manner. The apoptotic signaling cascades may proceed via proteolytic activation of caspase-2, change of mitochondrial membrane potential (Deltapsi(m)), release of cytochrome c and second mitochondria-derived activator of caspase/direct IAP binding protein with low pI (Smac/DIABLO), activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP). Increase in apoptosis-inducing factor and endonuclease G expressions in nuclei, and increase in Bax and Bak expressions and decrease in Bcl-X(L) expression on mitochondria were also observed in formosanin C-treated HT-29 cells. Attenuation of formosanin C-induced change of Deltapsi(m) by caspase-2 inhibitor (Z-VDVAC) implies that caspase-2 acts upstream of the mitochondria. Blockage of formosanin C-induced apoptotic process by using either permeability transition pore inhibitor (cyclosporine A) or caspase-9 inhibitor (Z-LEHD) demonstrates the necessity of mitochondria and caspase-9 in formosanin C-induced apoptosis of HT-29 cells. Taken together, the apoptotic mechanism of formosanin C in human colorectal cancer HT-29 cells involves activation of caspase-2 and the dysfunction of mitochondria.

Aurora-A overexpression enhances cell-aggregation of Ha-ras transformants through the MEK/ERK signaling pathway.

BACKGROUND: Overexpression of Aurora-A and mutant Ras (RasV12) together has been detected in human bladder cancer tissue. However, it is not clear whether this phenomenon is a general event or not. Although crosstalk between Aurora-A and Ras signaling pathways has been reported, the role of these two genes acting together in tumorigenesis remains unclear. METHODS: Real-time PCR and sequence analysis were utilized to identify Ha- and Ki-ras mutation (Gly -> Val). Immunohistochemistry staining was used to measure the level of Aurora-A expression in bladder and colon cancer specimens. To reveal the effect of overexpression of the above two genes on cellular responses, mouse NIH3T3 fibroblast derived cell lines over-expressing either RasV12 and wild-type Aurora-A (designated WT) or RasV12 and kinase-inactivated Aurora-A (KD) were established. MTT and focus formation assays were conducted to measure proliferation rate and focus formation capability of the cells. Small interfering RNA, pharmacological inhibitors and dominant negative genes were used to dissect the signaling pathways involved. RESULTS: Overexpression of wild-type Aurora-A and mutation of RasV12 were detected in human bladder and colon cancer tissues. Wild-type Aurora-A induces focus formation and aggregation of the RasV12 transformants. Aurora-A activates Ral A and the phosphorylation of AKT as well as enhances the phosphorylation of MEK, ERK of WT cells. Finally, the Ras/MEK/ERK signaling pathway is responsible for Aurora-A induced aggregation of the RasV12 transformants. CONCLUSION: Wild-type-Aurora-A enhances focus formation and aggregation of the RasV12 transformants and the latter occurs through modulating the Ras/MEK/ERK signaling pathway.

Regulation of CD151 by hypoxia controls cell adhesion and metastasis in colorectal cancer.

PURPOSE: The first step of metastasis is the detachment of cancer cells from the surrounding matrix and neighboring cells; however, how cancer cells accomplish this process remains unclear. Thus, we aimed to investigate the underlying mechanism that controls the early event of metastasis. EXPERIMENTAL DESIGN: One hundred and thirty-seven paired colorectal carcinoma and normal colon tissues were examined by immunohistochemical staining and Western blot for the expression of CD151, a member of the tetraspanin family that plays important roles in cell adhesion and motility. The effect of CD151 on cancer cell adhesion was investigated under normoxia and hypoxia conditions. RESULTS: The level of CD151 was down-regulated in colon cancer compared with the paired normal counterparts. Expression of CD151 was negatively regulated by hypoxia inducible factor-1-dependent hypoxic stress. Suppression of CD151 by hypoxia caused the detachment of cancer cells from the surrounding matrix and neighboring cells whereas restoration of CD151 expression during reoxygenation facilitated the adhesion capacity. Clinical examination further showed that metastasized cancer cells expressed a greater level of CD151 compared with that of primary tumor. CONCLUSION: Regulation of CD151 by oxygen tension may play an important role in cancer metastasis by regulating the detachment from the primary site and homing in the secondary site.

Association of gout and colorectal cancer in Taiwan: a nationwide population-based cohort study.

OBJECTIVES: This study aimed to determine colorectal cancer (CRC) risks among patients with gout through a follow-up study on a nationwide population-based cohort that included patients with gout and the general population in Taiwan. PARTICIPANT: From the Taiwan National Health Insurance Research Database, we identified 28 061 patients who were newly diagnosed with gout between 2000 and 2010 as the study cohort. We randomly selected 84 248 subjects matching in gender, age and baseline year as comparison cohort. The cohorts were followed up until CRC occurrence, withdrawal from the system of National Health Insurance, or Dec. 31, 2013. PRIMARY AND SECONDARY OUTCOME MEASURES: Cumulative incidences and incidence rate ratios (IRRs) of CRC between two cohorts were examined. The Cox proportional hazards model was used to evaluate risk factors associated with CRC development. RESULTS: During the 13-year follow-up, the incidence rate of CRC development in the gout cohort reached 2.44 per 1000 person-years, which was higher than the 2.13 per 1000 person-years in the control cohort (IRR=1.15; 95% CI 1.04 to 1.26). After adjusting for age, gender, urbanisation status and comorbidities, including hypertension, diabetes and hyperlipidaemia, gout showed no significant association with increased risk of CRC occurrence (adjusted HR=1.03; 95% CI 0.93 to 1.14). CONCLUSIONS: Similar risks of CRC incidence were observed in patients with and without gout in Taiwan. Allopurinol and colchicine are commonly used as urate-lowering drug and anti-inflammation medication in Taiwan and had been shown to reduce the risk of CRC incidence. Thus, further pharmaco-epidemiological studies should be carried out to specifically assess the role of allopurinol in the relationship between gout and CRC.