Metastasis Of Colorectal Carcinoma Research Articles

MiR-9-5p suppresses cell metastasis and epithelial-mesenchymal transition through targeting FOXP2 and predicts prognosis of colorectal carcinoma.

Colorectal carcinoma (CRC) is a common malignant tumor of the digestive tract that occurs in the colon, and the incidence is the third in the gastrointestinal tumor. Recently, the dysregulated expression of microRNA-9 (miR-9) has been identified in many human cancers. However, the special function of miR-9 in the progression of colorectal carcinoma (CRC) remains unknown. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of miR-9-5p in 72 pairs of CRC tissues and cell lines. The correlation between miR-9-5p expression and clinical features or prognosis of CRC patients was analyzed. In addition, we examined the mRNA and protein expression levels of forkhead box P2 (FOXP2) using Western blot analysis and qRT-PCR. The functions of miR-9-5p and FOXP2 were investigated using transwell assay and epithelial-mesenchymal transition (EMT). The relation between miR-9-5p and FOXP2 was confirmed by the dual-luciferase assay. In this study, down-regulation of miR-9-5p and up-regulation of the forkhead box P2 (FOXP2) were detected in CRC tissues and cell lines. Moreover, miR-9-5p was found to inhibit cell metastasis and EMT in CRC. In addition, it was confirmed that miR-9-5p directly targeted FOXP2 in CRC. Furthermore, FOXP2 had a carcinogenic effect on CRC. And the overexpression of FOXP2 weakened the suppressive effect of miR-9-5p in CRC. Of note, we observed found that the low expression of miR-9-5p and the high expression of FOXP2 were correlated with poor prognosis of CRC patients. MiR-9-5p suppressed cell metastasis and EMT through targeting FOXP2. Furthermore, dysregulation of miR-9-5p predicted the prognosis of CRC patients. Therefore, miR-9-5p may be a biomarker for cell metastasis and a prognostic factor for CRC patients. MiR-9-5p/FOXP2 axis will provide a new breakthrough in the diagnosis and treatment of CRC.

Genomic profiles of colorectal carcinoma with liver metastases and newly identified fusion genes.

Every year, approximately 1.2 million cases of colorectal carcinoma (CRC) are newly diagnosed worldwide. Although metastases to distant organs are often fatal complications of CRC, little information is known as to how such metastatic lesions are formed. To reveal the genetic profiles for CRC metastasis, we conducted whole‐exome RNA sequencing on CRC tumors with liver metastasis (LM) (group A, n = 12) and clinical stage‐matched larger tumors without LM (group B, n = 16). While the somatic mutation profiles were similar among the primary tumors and LM lesions in group A and the tumors in group B, the A‐to‐C nucleotide change in the context of “AAG” was only enriched in the LM regions in group A, suggesting the presence of a DNA damage process specific to metastasis. Genes already known to be associated with CRC were mutated in all groups at a similar frequency, but we detected somatic nonsynonymous mutations in a total of 707 genes in the LM regions, but not in the tumors without LM. Signaling pathways linked to such “LM‐associated” genes were overrepresented for extracellular matrix‐receptor interaction or focal adhesion. Further, fusions of the ADAP1 (ArfGAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF6, an ADAP1‐substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC. Additionally, recurrent ADAP1 fusion genes were unexpectedly discovered. As these fusions activate small GTPase, further experiments are warranted to examine their contribution to CRC carcinogenesis.

Acute kidney injury after liver resection in elderly patients

BackgroundAcute kidney injury (AKI) affects approximately 13% of patients undergoing major abdominal surgery, and is a common and important clinical sign of perioperative injury. The aim of our analysis was to identify risk factors for AKI in elderly patients with no known kidney disease at the time of surgery, and to evaluate their 30-day, 12-month and 5-year survival.MethodsWe performed a retrospective analysis on a group of 785 patients after liver resection to determine the incidence of complications (AKI – according to KDIGO classification, sepsis, cardiovascular and surgical complications). All patients had normal kidney function prior to surgery. We determined risk factors for the development of AKI for two groups of patients, stratified for age: patients younger than 65 years, and patients older than 65 years.ResultsThe incidence of complications was significantly higher in the group of patients older than 65 years (n = 76) than in younger patients (n = 119) (P = 0.0496). In the group of younger patients, significantly worse 30-day survival was observed for patients who developed AKI (P = 0.0004). We identified the following independent risk factors for AKI: male gender (HR 10,3834; P = 0,0238), histological identification of colorectal carcinoma metastases (HR 2,8651; P = 0,0499), surgery duration longer than 300 min (HR 6,0096; P < 0,0001), blood loss of more than 500 ml (HR 10,5857; P = 0,0012), and the need for more than 500 ml of fresh frozen plasma during surgery ml (HR 2,4878; P < 0,0317). Age was not confirmed to be an independent risk factor for AKI in our study.ConclusionApproaches to treatment should be highly individualized, with assessment of several variables. According to our findings, age should not present a contraindication for the indication of a patient for surgery.

SATB2-AS1 Suppresses Colorectal Carcinoma Aggressiveness by Inhibiting SATB2-Dependent Snail Transcription and Epithelial-Mesenchymal Transition.

Accumulating evidence suggests that long noncoding RNA (lncRNA) plays important regulatory roles in cancer biology. However, the involvement of lncRNA in colorectal carcinoma progression remains largely unknown, especially in colorectal carcinoma metastasis. In this study, we investigated the changes in lncRNA expression in colorectal carcinoma and identified a new lncRNA, the antisense transcript of SATB2 (SATB2-AS1), as a key regulator of colorectal carcinoma progression. SATB2-AS1 was frequently downregulated in colorectal carcinoma cells and tissues, and patients whose tumors expressed SATB2-AS1 at low levels had a shorter overall survival and poorer prognosis. Downregulation of SATB2-AS1 significantly promoted cell proliferation, migration, and invasion in vitro and in vivo, demonstrating that it acts as a tumor suppressor in colorectal carcinoma. SATB2-AS1 suppressed colorectal carcinoma progression by serving as a scaffold to recruit p300, whose acetylation of H3K27 and H3K9 at the SATB2 promoter upregulated expression of SATB2, a suppressor of colorectal carcinoma growth and metastasis. SATB2 subsequently recruited HDAC1 to the Snail promoter, repressing Snail transcription and inhibiting epithelial-to-mesenchymal transition. Taken together, these data reveal SATB2-AS1 as a novel regulator of the SATB2-Snail axis whose loss facilitates progression of colorectal carcinoma. SIGNIFICANCE: These data show that the lncRNA SATB2-AS1 mediates epigenetic regulation of SATB2 and Snail expression to suppress colorectal cancer progression.See related commentary by Li, p. 3536.

Histologic features and genomic alterations of primary colorectal adenocarcinoma predict growth patterns of liver metastasis.

BACKGROUNDDifferent histological growth patterns (HGPs) of colorectal carcinoma (CRC) liver metastasis are associated with patients’ prognosis and response to antiangiogenic therapy. However, the relationship between HGPs of liver metastasis and clinicopathological and genomic characteristics of primary cancer has not been well established.AIMTo assess whether certain clinicopathological and genomic features of primary CRC could predict the HGPs of liver metastasis.METHODSA total of 29 patients with paired resections of both primary CRC and liver metastasis were divided into two groups: A (15 cases with desmoplastic liver metastasis) and B (14 cases with replacement liver metastasis). Clinical information was obtained from patients’ charts. Mismatch repair proteins, BRAFV600E, and PD-L1 were evaluated by immunohistochemistry. Five cases were selected randomly from each group for whole exome sequencing (WES) analysis.RESULTSIn the primary tumor, expanding growth pattern, low tumor budding score (TBS), and Crohn’s disease-like response (CDR) were associated with desmoplastic liver metastasis and better overall survival, whereas infiltrating growth pattern alone of primary carcinoma could predict the replacement liver metastasis and worse overall survival (P < 0.05). On WES analysis, primary carcinoma with desmoplastic liver metastasis showed mutations in APC (4/5); TP53 (3/5); KRAS, PIK3CA, and FAT4 (2/5); BRCA-1, BRCA2, BRAF, and DNAH5 (1/5), whereas primary carcinoma with replacement liver metastasis showed mutations in APC and TP53 (3/5); KRAS, FAT4, DNH5, SMAD, ERBB2, ERBB3, LRP1, and SDK1 (1/5).CONCLUSIONThe HGPs, TBS, and CDR of primary CRC as well as the presence of specific genetic mutations such as those in PIK3CA could be used to predict the HGPs of liver metastasis, response to therapy, and patients’ prognosis.

&lt;p&gt;Jatrorrhizine inhibits colorectal carcinoma proliferation and metastasis through Wnt/β-catenin signaling pathway and epithelial–mesenchymal transition&lt;/p&gt;

PurposeJatrorrhizine (JAT) is a natural protoberberine alkaloid, possesses detoxification, bactericidal and hypoglycemic activities. However, its anti-cancer mechanism is not clear. This study aimed to investigate the mechanism of JAT through which inhibits colorectal cancer in HCT-116 and HT-29 cells.MethodsMTT assay and colony formation assay were used to check the cell proliferation ability. Cell apoptosis and cell cycle were measured by Hoechst 33342 staining and flow cytometry, respectively. Cell migration and invasion were detected by scratch wound healing assay and trans-well assay, respectively. Further, expression of related proteins was examined via Western blotting and the in vivo anti-cancer effect of JAT was confirmed by nude mice xenograft model.ResultsThe research showed that JAT inhibited the proliferation of HCT-116 and HT-29 cells with IC50 values of 6.75±0.29 μM and 5.29±0.13 μM, respectively, for 72 hrs. It has also showed a time dependently, cell cycle arrested in S phase, promoted cell apoptosis and suppressed cell migration and invasion. In addition, JAT inhibited Wnt signaling pathway by reducing β-catenin and increasing GSK-3β expressions. Increased expression of E-cadherin, while decreased N-cadherin, indicating that JAT treatment suppressed the process of cell epithelial–mesenchymal transition (EMT). In HCT-116 nude mice xenograft model, JAT inhibited tumor growth and metastasis, and induced apoptosis of tumor cells.ConclusionThis study demonstrated that JAT efficiently inhibited colorectal cancer cells growth and metastasis, which provides a new point for clinical treatment of colorectal cancer.

Activation of Slit2/Robo1 Signaling Promotes Tumor Metastasis in Colorectal Carcinoma through Activation of the TGF-β/Smads Pathway.

Slit2 (slit guidance ligand 2), a ligand of the Roundabout1 (Robo1) transmembrane receptor, is often overexpressed in colorectal carcinomas (CRCs). In this study, we performed data mining in the Metabolic gEne RApid Visualizer (MERAV) database and found that Slit2 and TGF-β1 (Transforming growth factor-β1) are highly expressed in carcinomas relative to those in tumor-free tissues from healthy volunteers or wild type mice. Furthermore, expression of Slit2 and TGF-β1 in CRCs increases with pathological stages. Serum levels of Slit2 in patients with CRC and in ApcMin/+ mice with spontaneous intestinal adenoma were significantly increased compared with those in healthy controls. Specific blockage of Slit2 binding to Robo1 inactivated TGF-β/Smads signaling and inhibited tumor cell migration and metastasis, which can be partially restored by treatment with TGF-β1. However, specific inhibition of TGF-β1/Smads signaling reduced CRC tumor cell migration and invasion without affecting cell proliferation. This study suggests that activation of Slit2/Robo1 signaling in CRC induces tumor metastasis partially through activation of the TGF-β/Smads pathway.

Effect of PTPRB on metastasis of colorectal carcinoma and induction of epithelial-mesenchymal transition.

e15099 Background: Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Metastasis and recurrence are believed to be responsible for limiting long-term survival of patients with CRC. Protein tyrosine phosphatase, receptor type B ( PTPRB) belongs to the protein tyrosine phosphatase family. Multiple studies have previously demonstrated that dysregulation of PTPRB function and expression has been shown to correlate with carcinogenesis and tumor progression in multiple cancer types. Methods: In this study, we used CRC cell lines to explore the expression of PTPRB and to analyze the biological function of PTPRB protein. Surgical tumor specimens were collected for immunohistochemical staining to evaluate PTPRB expression.Real-time polymerase chain reaction (PCR) and western blot analysis were used to confirm genes and proteins of interest, respectively. Results: PTPRB is expressed at significantly higher levels in CRC tissues compared to adjacent non-tumor tissues and in CRC cell lines with high metastasis potential. PTPRB knockdown decreased the number of invasive CRC cells in a vitro wound healing model, and also reduced tumor metastasis in vivo. Conversely, PTPRB overexpression decreased E-cadherin expression and promoted vimentin expression, while PTPRB knockdown had the opposite effect. Hypoxic conditions induced EMT and promoted metastasis in CRC cells, but these effects were eliminated by PTPRB knockdown. EMT blockade via TWIST1 knockdown inhibited the migration and invasiveness of CRC cells, and even increased PTPRB expression could not reverse this effect. Conclusions: PTPRB is upregulated in CRC and overexpression of PTPRB promotes the metastasis of CRC. Moreover, our study revealed the effect of PTPRB on promoting EMT, as reflected in increased vimentin and decreased E-cadherin expression. PTPRB is a novel therapeutic target for the treatment of CRC.

Significance of SATB2 expression in colon cancer and its differential diagnosis in digestive tract adenocarcinoma and ovarian primary and metastatic carcinoma

ObjectiveTo study the relationship between the expression of SATB2 in colonic adenocarcinoma and clinicopathological factors, and its role in the identification of ovarian digestive system metastatic adenocarcinoma. MethodsImmunohistochemistry was used to analyze the expression of SATB2 in 130 cases of colon adenocarcinoma, 46 cases of gastric adenocarcinoma, 47 cases of pancreatic ductal adenocarcinoma, 22 cases of cholangiocarcinoma, 53 cases of ovarian mucinous adenocarcinoma, and 38 cases of ovarian metastasis of colorectal carcinoma. Data was analyzed using SPSS 16.0 statistical software. ResultsThe positive expression rate of SATB2 in 130 cases of colon adenocarcinoma was 73.85% (96/130). The expression rate of SATB2 was significantly higher in well -moderately differentiated colon adenocarcinoma than in poorly differentiated adenocarcinoma (p<0.05); the expression rate was significantly higher in cases without tumor deposits than in cases with tumor deposits (p<0.05). The positive expression rate of SATB2 in ovarian metastases of colorectal adenocarcinoma was 81.58% (31/38). No positive expression of SATB2 was observed in other cancers. ConclusionLoss of expression of SATB2 is associated with poor differentiation of primary colon cancer and the formation of tumor deposits. SATB2 provides an ideal diagnostic marker for clinical surgeons to choose the right treatment plan.

Dystrophin Promotes Colorectal Carcinoma Metastasis and Exosome Secretion via Protein‐Protein Interaction with Rab GTPase 3C

RAB GTPases is involved in membrane trafficking (vesicle formation) and cell motility. Recently, exocytotic RABs has been noted that the exocytosis by RABs is correlated with drug resistance and immune response in tumorigenesis. However, the molecular mechanisms of exocytotic RABs in colorectal tumorigenicity remain unknown. RAB GTPase 3C (RAB3C) has been identified as the key component for exosome formation and exocytosis. In clinical colorectal carcinoma patient cohort, high RAB3C expression maintained its independent prognostic significance for both overall survival and disease‐free survival. We further established RAB3C‐based proteomics datasets and mass spectrometry analyses and found dystrophin (DMD) is upregulated in RAB3C ectopically overexpressed colon cancer cell lines. High DMD expression levels were found correlated with poor survival in colorectal cancer patient cohorts. Moreover, Dystrophin‐complex components including dystrobrevin (DTNA) and syntrophin (SNTA1/SNTB1) also showed the same prognosis trends in colorectal cancer patients. We further found that DMD is a rare mutant event in colorectal clinical cohort by next generation sequencing analysis. Our results showed that DMD could be stabilized by RAB3C through protein‐protein interaction. Besides, our results revealed RAB3C co‐localized with dystrophin complex by immunohistochemistry staining analysis. Merged DMD with RAB3C serves as a significant independent prognostic factor in colorectal cancer and is associated with several clinical parameters. In addition, dystrophin complex decreased cell membrane integrity and altered calcium channel activity for exocytosis. In summary, our results identified DMD is a new functional binding protein for RAB3C that affected colorectal carcinogenesis. These findings suggest a new therapeutic strategy for targeting cancer‐specific protein‐protein interactions in the treatment patients with colorectal cancer.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Role of HGF/c-Met in the treatment of colorectal cancer with liver metastasis.

The system of hepatocyte growth factor (HGF) and its receptor c‐Met plays a critical role in tumor invasive growth and metastasis. The mortality rate of colorectal cancer (CRC), one of the most commonly diagnosed malignancies, is increased by it gradual development into metastasis, most frequently in the liver. Overexpression of c‐Met, the protein tyrosine kinase receptor for the HCF/scatter factor, has been implicated in the progression and metastasis of human colorectal carcinoma. In this study, we aimed to investigate the role of c‐Met in CRC liver metastasis and illustrate the clinical impact of regulating HGF/c‐Met signaling in patients with CRC liver metastasis. We found that (I) higher levels of c‐Met expression (mRNA and Protein) in CRC liver metastasis than primary CRC by assessing the patient tissue samples; (II) a positive correlation of c‐Met expression with tumor stages of CRC liver metastasis, as well as c‐Met expression in CRC, live metastasis concurred with regional lymph node metastasis; (III) the clinical impact of downregulation of HGF/c‐Met signaling on the reduction of proliferation and invasion in CRC liver metastasis. Therefore, we demonstrate that the regulation of HGF/c‐Met pathways may be a promising strategy in the treatment of patients with CRC liver metastasis.

NPTX2 promotes colorectal cancer growth and liver metastasis by the activation of the canonical Wnt/\u03b2-catenin pathway via FZD6

Accumulating evidence from clinical and epidemiological studies has highlighted the close correlation between the individual risk of cancer and nervous system diseases. The expression of neuronal pentraxin 2 (NPTX2) is absent in Alzheimer’s disease, anxiety, and depression. Herein, we found that NPTX2 mRNA and protein expression was significantly upregulated in colorectal carcinoma (CRC). NPTX2 expression level gradually increased with CRC progression and was closely associated with poor prognosis. In vitro and in vivo studies demonstrated that NPTX2 promoted CRC proliferation and metastasis through the activation of the Wnt/β-catenin signaling pathway. As NPTX2 receptors are absent on CRC cells, NPTX2 was shown to physically interact with frizzled class receptor 6 (FZD6) to promote β-catenin translocation into the cell nucleus, resulting in an increase in the expression of MYC, cyclin D1, snail, and N-cadherin along with a decrease in the expression of E-cadherin. Knockdown of FZD6 expression with a small-interfering RNA almost completely reversed the proliferative effects of NPTX2 on CRC development. In conclusion, NPTX2, a molecule related to nervous system diseases, promotes CRC cell proliferation and metastasis through the activation of the Wnt/β-catenin pathway via direct interaction with FZD6.

Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin \u03b23 transcriptional activating and MAPK/AKT signalling

BackgroundLong noncoding RNAs (lncRNAs) have been indicated to play critical roles in cancer development and progression. LncRNA HOXD cluster antisense RNA1 (HOXD-AS1) has recently been found to be dysregulated in several cancers. However, the expression levels, cellular localization, precise function and mechanism of HOXD-AS1 in colorectal carcinoma (CRC) are largely unknown.MethodsReal-time PCR and in situ hybridization were used to detect the expression of HOXD-AS1 in CRC tissue samples and cell lines. Gain- and loss-of-function experiments were performed to investigate the biological roles of HOXD-AS1 in CRC cell line. RNA pull down, RNA immunoprecipitation and chromatin immunoprecipitation assays were conducted to investigate the mechanisms underlying the functions of HOXD-AS1 in CRC.ResultsWe observed that HOXD-AS1 was located in the nucleus of CRC cells and that nuclear HOXD-AS1 was downregulated in most CRC specimens and cell lines. Lower levels of nuclear HOXD-AS1 expression were associated with poor outcomes of CRC patients. HOXD-AS1 downregulation enhanced proliferation and migration of CRC cells in vitro and facilitated CRC tumourigenesis and metastasis in vivo. Mechanistic investigations revealed that HOXD-AS1 could suppress HOXD3 transcription by recruiting PRC2 to induce the accumulation of the repressive marker H3K27me3 at the HOXD3 promoter. Subsequently, HOXD3, as a transcriptional activator, promoted Integrin β3 transcription, thereby activating the MAPK/AKT signalling pathways.ConclusionOur results reveal a previously unrecognized HOXD-AS1-HOXD3-Integrin β3 regulatory axis involving in epigenetic and transcriptional regulation constitutes to CRC carcinogenesis and progression.

Novel radiomics signature predicts lymph node metastasis in T1 colorectal carcinoma.

506 Background: This study evaluates the predictive performance of radiomic features in metastasis of T1 colorectal carcinoma (CRC) to lymph nodes. Methods: A total of 10 200 CRC patients from our clinical cancer center included in this analysis. 225 eligible cases diagnosed with T1 CRC were included and divided into two groups: computed tomography (CT) image group (n = 82) and magnetic resonance image (MRI) group (n = 143) based on the preoperative image data available. A total of 548 radiomic features were extracted from each case and analyzed, and then a panel of radiomic features associated with lymph node metastases (LNM) were selected using Mann-Whitney U test. Combining these selected radiomic features and clinical data, the predictive performance for LNM was calculated using receiver operating characteristic (ROC) curves. Results: The prediction accuracy for LNM of T1 CRC could be improved to 0.88 by area under the receiver operating characteristic curve (AUC) through integration of one radiomic feature and three clinical indicators in CT group. In the group of contrast enhanced T1-weighted MRI (T1w-MRI), combination of two radiomic features and three clinical parameters present an AUC value of 0.85. In the group of T2-weighted MRI (T2w-MRI), combination of four radiomic features and five clinical characteristics identified T1 tumors with LNM with an AUC value of 0.87. Conclusions: The current study present a good predictive performance of combination of radiomic features with clinic characteristic in identifying T1 CRC with LNM, which may provide an important opportunity for us to make clinical treatment decision-making for T1 CRC patients.

Hepatic Endothelial Notch Activation Protects against Liver Metastasis by Regulating Endothelial-Tumor Cell Adhesion Independent of Angiocrine Signaling.

The interaction of tumor cells with organ-specific endothelial cells (EC) is an important step during metastatic progression. Notch signaling in organ-specific niches has been implicated in mediating opposing effects on organotropic metastasis to the lungs and the liver, respectively. In this study, we scrutinized the role of endothelial Notch activation during liver metastasis. To target hepatic EC (HEC), a novel EC subtype-specific Cre driver mouse was generated. Clec4g-Cretg/wt mice were crossed to Rosa26N1ICD-IRES-GFP to enhance Notch signaling in HEC (NICDOE-HEC). In NICDOE-HEC mice, hepatic metastasis of malignant melanoma and colorectal carcinoma was significantly reduced. These mice revealed reduced liver growth and impaired metabolic zonation due to suppression of hepatic angiocrine Wnt signaling. Hepatic metastasis, however, was not controlled by angiocrine Wnt signaling, as deficiency of the Wnt cargo receptor Wls in HEC of WlsHEC-KO mice did not affect hepatic metastasis. In contrast, the hepatic microvasculature in NICDOE-HEC mice revealed a special form of sinusoidal capillarization, with effacement of endothelial zonation functionally paralleled by reduced tumor cell adhesion in vivo. Notably, expression of endothelial adhesion molecule ICAM1 by HEC was significantly reduced. Treatment with an anti-ICAM1 antibody significantly inhibited tumor cell adhesion to HEC in wild-type mice confirming that Notch controls hepatic metastasis via modulation of HEC adhesion molecules. As endothelial Notch activation in the lung has been shown to promote lung metastasis, tumor therapy will require approaches that target Notch in an organ-, cell type-, and context-specific manner. SIGNIFICANCE: Manipulation of Notch signaling in the endothelium has opposing, organ-specific effects on metastasis to the lung and the liver, demonstrating that this pathway should be targeted in a cell- and context-specific fashion.

Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization

Cancer cells re-program their metabolic machinery to meet the requirements of malignant transformation and progression. Glutaminase 1 (GLS1) was traditionally known as a mitochondrial enzyme that hydrolyzes glutamine into glutamate and fuels rapid proliferation of cancer cells. However, emerging evidence has now revealed that GLS1 might be a novel oncogene involved in tumorigenesis and progression of human cancers. In this study, we sought to determine whether GLS1 implicated in invasion and metastasis of colorectal carcinoma, and its underlying molecular mechanism. By analyzing a large set of clinical data from online datasets, we found that GLS1 is overexpressed in cancers compared with adjacent normal tissues, and associated with increased patient mortality. Immunohistochemical analysis of GLS1 staining showed that high GLS1 expression is significantly correlated with lymph node metastasis and advanced clinical stage in colorectal cancer patients. To investigate the underlying mechanism, we analyzed the Cancer Genome Atlas database and found that GLS1 mRNA expression is associated with a hypoxia signature, which is correlated with an increased risk of metastasis and mortality. Furthermore, reduced oxygen availability increases GLS1 mRNA and protein expression, due to transcriptional activation by hypoxia-inducible factor 1. GLS1 expression in colorectal cancer cells is required for hypoxia-induced migration and invasion in vitro and for tumor growth and metastatic colonization in vivo.

APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production

The adenomatous polyposis coli (APC) gene plays a pivotal role in the pathogenesis of colorectal carcinoma (CRC) but remains a challenge for drug development. Long noncoding RNAs (lncRNAs) are invaluable in identifying cancer pathologies and providing therapeutic options for patients with cancer. Here, we identified a lncRNA (lncRNA-APC1) activated by APC through lncRNA microarray screening and examined its expression in a large cohort of CRC tissues. A decrease in lncRNA-APC1 expression was positively associated with lymph node and/or distant metastasis, a more advanced clinical stage, as well as a poor prognosis for patients with CRC. Additionally, APC could enhance lncRNA-APC1 expression by suppressing the enrichment of PPARα on the lncRNA-APC1 promoter. Furthermore, enforced lncRNA-APC1 expression was sufficient to inhibit CRC cell growth, metastasis, and tumor angiogenesis by suppressing exosome production through the direct binding of Rab5b mRNA and a reduction of its stability. Importantly, exosomes derived from lncRNA-APC1-silenced CRC cells promoted angiogenesis by activating the MAPK pathway in endothelial cells, and, moreover, exosomal Wnt1 largely enhanced CRC cell proliferation and migration through noncanonicial Wnt signaling. Collectively, lncRNA-APC1 is a critical lncRNA regulated by APC in the pathogenesis of CRC. Our findings suggest that an APC-regulated lncRNA-APC1 program is an exploitable therapeutic approach for the treatment of patients with CRC.

Predictive power of tumour budding for lymph node metastasis in colorectal carcinomas: A retrospective study.

Background & objectives:Tumour budding is a feature of epithelial-to-mesenchymal transformation that is characterized histologically within the tumour stroma by the presence of isolated cells or clusters of less than five cells which are different from the other malignant cells. This could be present around the invasive margin of the tumour, called peritumoural budding, or in the bulk of the tumour, called intratumoural budding. The aim of this study was to assess the predictive power of tumour budding for lymph node metastasis and its relationship with other features of tumour progression in colorectal carcinoma (CRC).Methods:Preoperative colonoscopic biopsies and consecutive resection specimens from 80 patients of colorectal cancer were taken. In the biopsy, intratumoural budding was looked for and graded. In the resection, peritumoural budding was seen and graded along with other features such as grade of the tumour, lymphovascular emboli and tumour border configuration.Results:Intratumoural budding was seen in 23 per cent (18/80) and peritumoural in 52 per cent (42/80) of cases. Intratumoural budding was associated with the presence of lymphovascular emboli (P=0.002) and irregular tumour border configuration (P=0.004). Peritumoural budding was also significantly associated with the presence of lymphovascular emboli and irregular margins (P<0.001). Both intra- and peritumoural budding were not associated with the grade of the tumour. Both intra- and peritumoural budding had a significant association with lymph node metastasis (LNM) (P<0.001).Interpretation & conclusions:Our findings indicate that tumour budding in preoperative biopsy and resection specimens may predict a possibility of finding LNM in patients with CRC.

Low expression of MUC2 is associated with longer disease-free survival in patients with colorectal carcinoma.

Background/Aim:The objective of this study was to investigate the relationship between MUC2 immunostaining and clinicopathological characteristics in a subset of colorectal carcinomas (CRCs).Materials and Methods:A total of 128 CRCs, 50 local nodal metastases, and 42 normal colonic mucosae were retrieved from the archives at the Department of Pathology at King Abdulaziz University, Jeddah, Saudi Arabia. Immunohistochemistry was performed using anti-MUC2 antibody. A cut-off of 25% of positive immunostaining was used to define low and high immunostaining. Statistical tests were used to determine the association of MUC2 with clinicopathological characteristics and survival.Results:MUC2 immunostaining was observed in 66.7% in normal colonic mucosa. Low MUC2 immunostaining was higher in primary CRC (P = 0.003) and nodal metastasis (80%) (P < 0.001). There was significant association of low MUC2 immunostaining in CRC with age group below 60 years (P = 0.05) and occurrence of lymphovascular invasion (P = 0.034). Other clinicopathological parameters were not correlated with MUC2 immunostaining. Regression analysis revealed that low MUC2 immunostaining was an independent predictor of lymphovascular invasion (P = 0.041). In the Kaplan–Meier survival analysis, there was a significant longer disease-free survival in patients with low MUC2 immunostaining (P = 0.045). However, there was no association between MUC2 immunostaining and overall survival (P = 0.601).Conclusion:MUC2 immunostaining may have distinct clinical significance and provide valuable information and could be considered as an important independent prognostic factor while planning the adjuvant therapy in CRC. In future perspective, characterization of MUC2 immunostaining on a large number of cases and molecular studies may be needed.

Resection of hepatic metastatics from colorectal carcinoma. Factors related with recurrence and disease-free survival

Background: Surgery has become the standard treatment for patients with stage IV colorectal carcinoma and liver metastasis. Methods: From 2010-2015: 158 patients with liver metastases (142 CRC metastases that). We analyzed long-term results,actuarial survival and DFS, and compared risk factors with log-rank and chi-square (significance level p <0.05). Results: 72 metachronous (51%) and 70 synchronous metastases: 14 simultaneous resection, 14 liver-first, and colon-liver resection in 60% . With a mean follow-up of 23.7±16 months presented tumor recurrence 53(46.5%). At end, 55 patients were alive without tumor recurrence (41%). DFS at 1, 3 and 5 years is 65%, 37.9% and 32.1%, respectively, with an mean DFS interval of 33.6±2.96 months. Variables related to the recurrence: bilobar or segment I location,inverse surgery, second hepatectomies, presence of vascular invasion and R1 resection . Variables related to DFS: multicentric tumors, reverse surgery, rehepatectomies, vascular invasion and R1 resection. The use of preoperative chemotherapy, the type of resection or the need for transfusion has not been linked to long-term results. Conclusion: Resection of CCR hepatic metastases is the treatment of choice with 5-year DFS about 32% and mean DFS of 34 months. Initial hepatic resection in synchronous metastases has been associated with worse DFS as well as second resections. Neither the type of resection (major hepatectomy or atypical resection) nor the use or not of preoperative chemotherapy have been related to recurrence.