WNT signaling activation in colorectal cancers (CRCs) occurs through APC inactivation or β-catenin mutations. Both processes promote β-catenin nuclear accumulation, which up-regulates ...epithelial-to-mesenchymal transition (EMT). We investigated β-catenin localization, transcriptome, and phenotypic differences of HCT116 cells containing a wild-type (HCT116-WT) or mutant β-catenin allele (HCT116-MT), or parental cells with both WT and mutant alleles (HCT116-P). We then analyzed β-catenin expression and associated phenotypes in CRC tissues. Wild-type β-catenin showed membranous localization, whereas mutant showed nuclear localization; both nuclear and non-nuclear localization were observed in HCT116-P. Microarray analysis revealed down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT without E-cadherin dysregulation. We found that ZEB1 is a critical EMT factor for mutant β-catenin-mediated loss of E-cadherin and Claudin-7 in HCT116-P and HCT116-MT cells. We also demonstrated that E-cadherin binds to both WT and mutant β-catenin, and loss of E-cadherin releases β-catenin from the cell membrane and leads to its degradation. Alteration of Claudin-7, as well as both Claudin-7 and E-cadherin respectively caused tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased cell motility, and subsequent AJ loss further up-regulated that. Immunohistochemistry analysis of 101 CRCs revealed high (14.9%), low (52.5%), and undetectable (32.6%) β-catenin nuclear expression, and high β-catenin nuclear expression was significantly correlated with overall survival of CRC patients (P = 0.009). Our findings suggest that β-catenin activation induces EMT progression by modifying cell-cell junctions, and thereby contributes to CRC aggressiveness.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Among colorectal cancers (CRCs), high-frequency microsatellite instability (MSI-H) is associated with a better prognosis, compared with low-frequency MSI or microsatellite stability (MSI-L/MSS). ...However, it is unclear whether MSI affects the prognosis of recurrent CRCs.
This study included 2940 patients with stage I-III CRC who underwent complete resection. The associations of MSI status with recurrence patterns, disease-free survival (DFS), overall survival from diagnosis to death (OS1), and overall survival from recurrence to death (OS2) were analysed.
A total of 261 patients (8.9%) had MSI-H CRC. Patients with MSI-H CRC had better DFS, compared to patients with MSI-L/MSS CRC (hazard ratio (HR): 0.619, P<0.001). High-frequency microsatellite instability CRC was associated with more frequent local recurrence (30.0% vs 12.0%, P=0.032) or peritoneal metastasis (40.0% vs 12.3%, P=0.003), and less frequent lung (10.0% vs 42.5%, P=0.004) or liver metastases (15.0% vs 44.7%, P=0.01). Recurrent MSI-H CRC was associated with worse OS1 (HR: 1.363, P=0.035) and OS2 (HR: 2.667, P<0.001). An analysis of patients with colon cancer yielded similar results.
Recurrence patterns differed between MSI-H CRC and MSI-L/MSS CRC, and recurrent MSI-H CRCs had a worse prognosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background and Aims
Biliary tract cancer (BTC) exhibits diverse molecular characteristics. However, reliable biomarkers that predict therapeutic responses are yet to be discovered. We aimed to ...identify the molecular features of treatment responses to chemotherapy and immunotherapy in BTCs.
Approach and Results
We enrolled 121 advanced BTC patients (68 cholangiocarcinomas 33 intrahepatic, 35 extrahepatic, 41 gallbladder cancers, and 12 Ampulla of Vater cancers) whose specimens were analyzed by clinical sequencing platforms. All patients received first‐line palliative chemotherapy; 48 patients underwent programmed death 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) blockade therapy after failed chemotherapy. Molecular and histopathological characterization was performed using targeted sequencing and immunohistochemical staining to investigate treatment response‐associated biomarkers. Genomic analysis revealed a broad spectrum of mutational profiles according to anatomical location. Favorable responses to chemotherapy were observed in the small‐duct type compared with the large‐duct type intrahepatic cholangiocarcinoma, with frequent mutations in BRCA1‐associated protein‐1/isocitrate dehydrogenase 1/2 and KRAS proto‐oncogene, GTPase/SMAD family member 4 genes, respectively. The molecular features were further analyzed in BTCs, and transforming growth factor beta and DNA damage response pathway‐altered tumors exhibited poor and favorable chemotherapy responses, respectively. In PD‐1/PD‐L1 blockade‐treated patients, KRAS alteration and chromosomal instability tumors were associated with resistance to immunotherapy. The majority of patients (95.0%) with these resistance factors show no clinical benefit to PD‐1/PD‐L1 blockade and low tumor mutational burdens. Low tumor‐infiltrating lymphocyte (TIL) density in tumors with these resistance factors indicated immune‐suppressive tumor microenvironments, whereas high intratumoral TIL density was associated with a favorable immunotherapy response.
Conclusions
This study proposes predictive molecular features of chemotherapy and immunotherapy responses in advanced BTCs using clinical sequencing platforms. Our result provides an intuitive framework to guide the treatment of advanced BTCs benefiting from therapeutic agents based on the tumors’ molecular features.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose: Although microRNAs have recently been recognized as riboregulators of gene expression, little is known about microRNA expression
profiles in serous ovarian carcinoma. We assessed the ...expression of microRNA and the association between microRNA expression
and the prognosis of serous ovarian carcinoma.
Experimental Design: Twenty patients diagnosed with serous ovarian carcinoma and eight patients treated for benign uterine disease between December
2000 and September 2003 were enrolled in this study. The microRNA expression profiles were examined using DNA microarray and
Northern blot analyses.
Results: Several microRNAs were differentially expressed in serous ovarian carcinoma compared with normal ovarian tissues, including
miR-21, miR-125a, miR-125b, miR-100, miR-145, miR-16 , and miR-99a , which were each differentially expressed in >16 patients. In addition, the expression levels of some microRNAs were correlated
with the survival in patients with serous ovarian carcinoma. Higher expression of miR-200, miR-141, miR-18a, miR-93 , and miR-429 , and lower expression of let-7b , and miR-199a were significantly correlated with a poor prognosis ( P < 0.05).
Conclusion: Our results indicate that dysregulation of microRNAs is involved in ovarian carcinogenesis and associated with the prognosis
of serous ovarian carcinoma.
Gain‐of‐function mutations of KIT are pathognomonic in sporadic gastrointestinal stromal tumors (GISTs). Several microRNAs have been shown to be dysregulated in GISTs and impact KIT expression. ...Little is known though on KIT‐independent targets of KIT‐regulating mRNAs. We sought to investigate how miR‐494 inhibits GIST proliferation and to identify novel target gene. We used microarray‐based gene expression analyses to identify pathways and target genes affected by miR‐494. The expressional relationship between survivin and miR‐494 was determined in 35 GIST tissues. Cell proliferation assay, FACS analysis, colony formation assay, promoter assays and chromatin immunoprecipitation (ChiP) were performed to clarify the roles of survivin in GIST progression. Gene expression microarray analysis revealed that miR‐494 inhibited GISTs by affecting multiple genes in the cell cycle pathway. Survivin (BIRC5) was a key target of miR‐494, and its expression showed an inverse correlation with miR‐494 expression in 35 GIST tissues (Pearson's correlation coefficient, r = −0.418, p = 0.012). Downregulation of survivin inhibited proliferation and colony formation, and resulted in cell cycle alteration. Induced survivin overexpression relieved miR‐494‐mediated inhibition of GIST progression. Targeting PI3K effectively suppressed proliferation of GISTs with downregulation of survivin. Survivin also regulated KIT expression at the transcription level. Immunohistochemical analysis using 113 GISTs revealed that survivin expression was significantly correlated with overall survival of GIST patients (p = 0.004). Our findings indicated that miR‐494 synergistically suppressed GISTs by concomitantly targeting survivin and KIT.
What's new?
Gain‐of‐function mutations of KIT are pathognomonic in sporadic gastrointestinal stromal tumors (GISTs). Several microRNAs have also been shown to be dysregulated in GISTs and impact KIT expression. However, still little is known on KIT‐independent targets of KIT‐regulating mRNAs. Here, the authors report that miR‐494 induces alteration of the cell cycle pathways in GISTs by downregulating survivin, which functions as a transcription factor of KIT, accompanying effective blockade of the PI3K pathway that both KIT and survivin belong to. Based on these findings, miR‐494 may play important roles during GIST tumorigenesis and be used as a potent agent to treat GISTs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The aim of this study is to compare the short-term results between robotic-assisted low anterior resection (R-LAR), using the da Vinci
®
Surgical System, and standard laparoscopic low ...anterior resection (L-LAR) in rectal cancer patients.
Methods
113 patients were assigned to receive either R-LAR (
n
= 56) or L-LAR (
n
= 57) between April 2006 and September 2007. Patient characteristics, perioperative clinical results, complications, and pathologic details were compared between the groups. Moreover, macroscopic grading of the specimen was evaluated.
Results
Patient characteristics were not significantly different between the groups. The mean operation time was 190.1 ± 45.0 min in the R-LAR group and 191.1 ± 65.3 min in the L-LAR group (
P
= 0.924). The conversion rate was 0.0% in the R-LAR groups and 10.5% in the L-LAR group (
P
= 0.013). The serious complication rate was 5.4% in the R-LAR group and 19.3% in the L-LAR group (
P
= 0.025). The specimen quality was acceptable in both groups. However, the mesorectal grade was complete (
n
= 52) and nearly complete (
n
= 4) in the R-LAR group and complete (
n
= 43), nearly complete (
n
= 12), and incomplete (
n
= 2) in the L-LAR group (
P
= 0.033).
Conclusion
R-LAR was performed safely and effectively, using the da Vinci
®
Surgical System. The use of the system resulted in acceptable perioperative outcomes compared to L-LAR.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The diagnosis of solid pseudopapillary neoplasms (SPNs) is challenging because some SPNs share many similar morphological and immunohistochemical features with other pancreatic neoplasms. In this ...study, we investigated potential diagnostic markers of SPN. Based on the SPN-specific upregulated genes from a previous DNA microarray and proteome study, we selected six immunohistochemical markers beta-catenin, androgen receptor (AR), lymphoid enhancer-binding factor 1 (LEF1), transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3), fused in sarcoma (FUS), and WNT inhibitory factor 1 (WIF-1). We also evaluated the Ki-67 proliferative index to investigate its associations with prognosis. To validate these markers, we studied 91 SPNs as well as 51 pancreatic ductal carcinomas (PDC) and 48 neuroendocrine tumors (NET) as controls. We found frequent and diffuse nuclear expressions of β-catenin (98.9%), AR (81.3%), LEF1 (93.4%), TFE3 (74.7%), FUS (84.6%), and cytoplasmic expression of WIF-1 (96.7%) in SPNs. In contrast, PDCs and NETs showed no expression. (
< 0.001). When beta-catenin, LEF1, and TFE3 staining were combined, the sensitivity and specificity were 100% and 91.9%, respectively. Four (4.4%) SPNs showed distant metastasis and these tumors were associated with a relatively high Ki-67 proliferative index (≥ 5%;
= 0.013). We identified LEF1, TFE3, and AR as putative diagnostic markers of SPN, auxiliary to β-catenin. Incorporated into an immunohistochemical panel, these markers could be beneficial to distinguish SPN from PDC and NET. In addition, we suggest that the Ki-67 proliferative index can be a predictive marker of metastasis in SPNs.
This study investigated whether MSI status can be used as a prognostic biomarker and whether it is helpful for predicting which patients will benefit from 5‐FU based adjuvant chemotherapy. Between ...2005 and 2008, an MSI status examination was performed in 1,990 gastric cancer patients who had undergone curative gastrectomy for gastric adenocarcinoma. MSI was analyzed by PCR amplification with fluorescent dye‐labeled primers of mononucleotide markers (BAT25 and BAT26) and dinucleotide markers (D5S346, D2S123 and D17S250) specific to the microsatellite loci. Patients with MSI‐H tumors accounted for 8.5% (n = 170) of the total study population. They tended to be older and female and to have distal tumor location, lower tumor stage, intestinal type of Lauren classification and differentiated histological type. The disease‐free survival curves showed no significant differences between MSS/MSI‐L and MSI‐H patients at each stage of I, II, III and IV. In gastric cancer patients with stage II and III, 5‐FU‐based adjuvant chemotherapy showed better disease‐free survival in the MSS/MSI‐L group, but showed no benefits in the MSI‐H group. By multivariate analysis, patients with MSS/MSI‐L tumors benefited from 5‐FU‐based adjuvant chemotherapy in terms of tumor disease‐free survival. MSI status in gastric cancer is not itself a prognostic indicator. However, it appears to be a possible guidance for the use of 5‐FU‐based chemotherapy in stage II and III gastric cancers after R0 resection.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Golgi apparatus plays a central role in the intracellular transport of macromolecules. However, molecular mechanisms of Golgi-mediated lipid transport remain poorly understood. Here, we show that ...genetic inactivation of the Golgi-resident protein GRASP55 in mice reduces whole-body fat mass via impaired intestinal fat absorption and evokes resistance to high-fat diet induced body weight gain. Mechanistic analyses reveal that GRASP55 participates in the Golgi-mediated lipid droplet (LD) targeting of some LD-associated lipases, such as ATGL and MGL, which is required for sustained lipid supply for chylomicron assembly and secretion. Consequently, GRASP55 deficiency leads to reduced chylomicron secretion and abnormally large LD formation in intestinal epithelial cells upon exogenous lipid challenge. Notably, deletion of dGrasp in Drosophila causes similar defects of lipid accumulation in the midgut. These results highlight the importance of the Golgi complex in cellular lipid regulation, which is evolutionary conserved, and uncover potential therapeutic targets for obesity-associated diseases.
Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathologic parameters, a clinical test that can discriminate patients with good outcomes from those ...with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment.
Microarray technologies were used to generate and analyze gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients.
We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the six-gene signature in an additional independent cohort.
The risk score derived from the six-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy.
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