Metastasis Of Colon Adenocarcinoma Research Articles

Modulation of SRC by SNTB1 activates the Hippo-YAP pathway during colon adenocarcinoma metastasis

BackgroundColon adenocarcinoma (COAD) ranks as the third most prevalent and lethal cancer in 2020, with metastasis being the primary cause of cancer-related mortality. A comprehensive understanding of the mechanism underlying distant metastasis is imperative for enhancing the prognosis and quality of life of patients with COAD.MethodsThis study employed gene set enrichment analysis (GSEA) on RNA-sequencing data from 408 patients with COAD in The Cancer Genome Atlas (TCGA) database. GSEA analysis was applied to find the significant hallmark gene set, and genes in the significant hallmark gene set was performed by univariate Cox regression to select the key gene. Then, multivariate Cox regression model was constructed. And various databases were utilized to validate and find the significant oncoprotein and hallmark gene set of the key gene. In addition, the expression of key regulators in para-carcinoma tissue, colon cancer and distant metastases samples were detected by real-time PCR, Immunohistochemistry and Western blot. Additionally, the biological functions were examined by in vitro and in vivo experiments. The scRNA-seq and CellphoneDB were performed to explore cell characters in COAD and the potential mechanism of metastasis.ResultsThe regulatory network analysis revealed SRC/YAP1 as the most significant oncoprotein and signature gene set associated with SNTB1. Moreover, significant SNTB1 overexpression in COAD metastatic tissues was observed compared to para-carcinoma and primary COAD tissues. Co-immunoprecipitation assays demonstrated the formation of a complex between SNTB1 and SRC proteins. Furthermore, the overexpression of SNTB1 enhanced the proliferation, migration and invasion capacities of COAD cell lines. Caudal vein injection of COAD cells overexpressing SNTB1 in nude mice resulted in increased tumour growth and metastasis to the lung, liver and bone. Finally, single cell RNA-seq revealed alterations in the cellular subtypes of COAD, and CellphoneDB indicated that the interaction between cancer cells exhibiting high SNTB1 expression and enterocytes promoted EMT through cellular communications involving TGF-β, accelerating metastasis in COAD.ConclusionThis study postulates that SNTB1 interacts with SRC to activate the Hippo-YAP pathway, thereby promoting COAD metastasis. Furthermore, cellular communication with enterocytes promotes EMT, facilitating metastasis. These findings propose novel therapeutic targets for preventing or treating metastatic COAD.

Pancancer analysis of NDUFA4L2 with focused role in tumor progression and metastasis of colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a prevalent gastrointestinal malignant disease with a high mortality rate, and identification of novel prognostic biomarkers and therapeutic targets is urgently needed. Although NDUFA4L2 has high expressions in various tumors and affects tumor progression, its role in COAD remains unclear. The role of NDUFA4L2 in COAD was analyzed utilizing datasets available from public databases including The Cancer Genome Atlas, The Genotype-Tissue Expression (GTEx), Gene Expression Omnibus, Alabama Cancer Database (UALCAN), and The Human Protein Atlas databases. The prognostic value of NDUFA4L2 was determined using Kaplan-Meier analysis and Cox regression analysis. To investigate the possible mechanism underlying the role of NDUFA4L2 in COAD, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were employed. The correlation between NDUFA4L2 expression and immune cell infiltration levels was examined through single-sample gene set enrichment analysis (ssGSEA). The NDUFA4L2 expression levels in COAD patients and cell lines were validated through immunohistochemistry, immunofluorescence, qRT-PCR, and Western blot. Wound healing assay was also performed to evaluate the effect of NDUFA4L2 on COAD metastasis. Furthermore, the NDUFA4L2 mediated competing endogenous RNA (ceRNA) regulatory network was predicted and constructed through a variety of databases. The comprehensive pan-cancer analysis showed that NDUFA4L2 possesses diagnostic and prognostic value in many cancers, especially in COAD. GO-KEGG and GSEA analyses indicated that NDUFA4L2 was associated with multiple biological functions including epithelial-mesenchymal transition and adaptation to hypoxia. The ssGSEA analysis showed that NDUFA4L2 expression was associated with immune infiltration. In vitro experiments confirmed upregulation of NDUFA4L2 in COAD tissues and cell lines, and NDUFA4L2 overexpression significantly promoted migration of COAD cells. In addition, the C9orf139 /miR-194-3p axis was speculated as the possible upstream regulators of NDUFA4L2 in COAD. This study demonstrated that NDUFA4L2 upregulation was correlated with tumor progression, relapsed prognosis and aggressive migration of COAD, suggesting that NDUFA4L2 can act as an effective prognostic biomarker and a promising therapeutic target for COAD treatment.

Identification of novel diagnostic biomarkers associated with liver metastasis in colon adenocarcinoma by machine learning

BackgroundLiver metastasis is one of the primary causes of poor prognosis in colon adenocarcinoma (COAD) patients, but there are few studies on its biomarkers.MethodsThe Cancer Genome Atlas (TCGA)-COAD, GSE41258, and GSE49355 datasets were acquired from the public database. Differentially expressed genes (DEGs) between liver metastasis and primary tumor samples in COAD were identified by limma, and functional enrichment analysis were performed. MuTect2 and maftools were used to measure somatic mutation rates, while ADTEx was used to measure copy number variations (CNVs). The intersection of three machine learning methods, support vector machine (SVM), Random Forest, and least absolute shrinkage and selection operator (LASSO), is utilized to screen biomarkers, and their diagnostic performance is subsequently validated. The correlation between biomarkers and immune cells infiltration was analyzed by Spearman method.Results47 DEGs between liver metastasis and primary tumor samples in COAD were obtained, which were mainly enriched in the complement and coagulation, extracellular matrix (ECM), and peptidase regulator activity, etc. 38 out of 47 DEGs had mutations and exhibited a high frequency of CNV amplification or deletion. Furthermore, 3 biomarkers (MMP3, MAB21L2, and COLEC11) were screened, which showed good diagnostic performance. The proportion of multiple immune cells, such as B cells naive, T cells CD4 naive, Monocytes, and Dendritic cells resting, was higher in liver metastasis samples than that in primary tumor samples. Meanwhile, MMP3, MAB21L2, and COLEC11 exhibited an outstanding correlation with immune cells infiltration.ConclusionIn short, 3 biomarkers with good diagnostic efficacy were identified, providing a new perspective of therapeutic targets for liver metastasis in COAD.

Kolizija primarnog adenokarcinoma pluća sa metastazom adenokarcinoma debelog creva - prikaz slučaja

Introduction. Collision tumors occur when two tumors of different histological origin develop simultaneously at the same site, such as sarcoma and carcinoma combinations, carcinoma and lymphoma combinations, or others. Notably, collision tumors are less common in the lungs compared to other organs. Case report. A 65-year-old woman with a history of surgically and chemotherapeutically treated colon adenocarcinoma underwent a regular chest radiographic check-up at a hospital. A follow-up examination and computed tomography revealed two oval lesions in the right lung lobe, later confirmed through histopathological and immunohistochemical analysis. One lesion was identified as primary lung adenocarcinoma, while the other was a metastasis of colon adenocarcinoma. Diagnosis of lesions with distinct histological origins relies on determining the expression of specific markers. Lung adenocarcinoma typically expresses TTF-1 in 90% of cases, while metastases originating from colonic adenocarcinoma often exhibit CDX2 marker expression in 99% of cases. Conclusion. Several theories attempt to explain the formation of collision tumors. The first hypothesis suggests that their origin lacks a specific pattern or predictable cause. The second hypothesis proposes that environmental changes, influenced by carcinogenic stimuli, promote the simultaneous growth of two tumors. Lastly, it is hypothesized that tumors modify the organ's microenvironment, increasing the likelihood of nearby metastatic colonization. To ensure effective treatment of collision tumors, accurate and precise diagnosis, along with a comprehensive understanding of the tumor's characteristics, is crucial.

KLF7 promotes colon adenocarcinoma progression through the PDGFB signaling pathway.

Colon adenocarcinoma (COAD) is the most common malignancy of the digestive tract, which is characterized by a dismal prognosis. No effective treatment has been established presently, thus there is an urgent need to understand the mechanisms driving COAD progression in order to develop effective therapeutic approaches and enhance clinical outcomes. In this study, we found that KLF7 is overexpressed in COAD tissues and correlated with clinicopathological features of COAD. Both gain-of-function and loss-of-function experiments have unequivocally demonstrated that overexpression of KLF7 promotes the growth and metastasis of COAD in vitro and in vivo, while KLF7 knockdown attenuated these effects. Mechanistically, our findings reveal that KLF7 can specifically bind to the promoter region of PDGFB (TGGGTGGAG), thus promoting the transcription of PDGFB and increasing its secretion. Subsequently, secreted PDGFB facilitates the progression of COAD by activating MAPK/ERK, PI3K/AKT, and JAK/STAT3 signaling pathways through PDGFRβ. Additionally, we found that sunitinib can block PDGFB signaling and inhibit COAD progression, offering a promising therapeutic strategy for COAD treatment.

MCM5 is an oncogene of colon adenocarcinoma and promotes progression through cell cycle control

Many patients with colon adenocarcinoma (COAD) are diagnosed at an advanced stage, and the molecular mechanism of COAD progression is intricate and controversial. Therefore, there is an urgent need to identify more novel prognosis biomarkers for COAD and elucidate the molecular mechanism of this disease. The present study aimed to screen out key genes correlated with COAD prognosis. In this study, a key module was identified and four hub genes (MCM5 (encoding minichromosome maintenance complex component 5), NOLC1 (encoding nucleolar and coiled-body phosphoprotein 1), MYC (encoding MYC proto-oncogene, BHLH transcription factor), and CDK4 (encoding cyclin dependent kinase 4)) were selected that correlated with COAD prognosis, based on the GSE9348 dataset in Gene Expression Omnibus database. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that MCM5 correlated with the cell cycle. Furthermore, MCM5 expression was upregulated in tumor tissues of patients with COAD compared with that in adjacent tissues, based on various databases, including The Cancer Genome Atlas, the Clinical Proteomic Tumor Analysis Consortium database, and the Human Protein Atlas database. Small interfering RNA-mediated knockdown of MCM5 inhibited the cell cycle and migration of colorectal cancer cells in vitro. And western blotting results indicated that factors correlated with cell cycle (CDK2/6, Cyclin D3, P21) were downregulated after knockdown of MCM5 in vitro. Besides, downregulation of MCM5 was demonstrated to inhibit lung metastasis of COAD in nude mice model. In conclusion, MCM5 is an oncogene of COAD that promotes COAD progression via cell cycle control.

The crosstalk between anoikis and epithelial-mesenchymal transition and their synergistic roles in predicting prognosis in colon adenocarcinoma.

Anoikis and epithelial-mesenchymal transition (EMT) are significant phenomena occurring in distant metastasis of colon adenocarcinoma (COAD). A comprehensive understanding of their crosstalk and the identification of key genes are vital for treating the distant metastasis of COAD. The objective of this study was to design and validate accurate prognostic predictors for COAD patients based on the anoikis and EMT processes. We obtained gene signatures from various databases and performed univariate and multivariate Cox regression analyses, principal component analysis (PCA). The COAD patients were categorized into the worst prognosis group, the Anoikis Potential Index (API) Low + EMT Potential Index (EPI) High group and the others group. Then we utilized gene set enrichment analysis (GSEA) to identify differentially expressed genes and to establish a prognostic risk model. The model classified patients into high- or low-risk groups, with patients in the high-risk group displaying worse survival status. A nomogram was established to predict overall survival rates, demonstrating high specificity and sensitivity. Additionally, we connected the risk model to the tumor microenvironment (TME) using single-sample GSEA and the MCP counter tool, as well as evaluated the sensitivity to common chemotherapeutic drugs, such as Gefitinib and Gemcitabine. Lastly, cell and tissue experiments suggested a positive correlation among anoikis resistance, EMT, and liver/lung metastasis of COAD. This is the first study to comprehensively analyze the crosstalk between anoikis and EMT and offers new therapeutic targets for COAD metastasis patients.

Hypomethylation-mediated LINC00346 facilitates cell phenotype progression of colon adenocarcinoma via modulating miR-589-5p/CCL5

The study aimed to investigate the role of LINC00346 in colon adenocarcinoma (COAD) metastasis. qRT-PCR, methylation-specific PCR, immunohistochemistry and western blotting were used to measure the expression levels of LINC00346, miR-589–5p, and CCL5 in COAD cells and tissues. Dual-luciferase assays, RNA immunoprecipitation, and RNA pull-down were used to validate the targeting relationship between LINC00346/CCL5 and miR-589–5p. In vivo experiments were conducted to study the impact of LINC00346 on COAD progression. MTT, colony formation assay, transwell assay and wound healing assay were used to detect the COAD cell proliferation, colony formation, invasion and migration. The results showed that COAD cells and tissues had high expression of LINC00346 and CCL5, and low expression of miR-589–5p. LINC00346 expression was upregulated due to DNA hypomethylation in its promoter region. miR-589–5p targets both LINC00346 and CCL5. LINC00346 facilitated the malignant progression of COAD by preventing the degradation of CCL5 via competitively binding to miR-589–5p. Rescue experiments indicated a ceRNA pattern consisting of LINC00346, miR-589–5p, and CCL5. Overall, LINC00346 promotes COAD progression via the miR-589–5p/CCL5 axis and may be a potential therapeutic target for COAD.

Synchronous pancreatic metastasis of left colon adenocarcinoma: a case report with review of the literature

Synchronous pancreatic metastasis of left colon adenocarcinoma: a case report with review of the literature

Novel characterization discoveries of ferroptosis-associated molecules in COAD microenvironment based TCGA data.

Background and Objective: One of the most recent forms of programmed cell death, ferroptosis, is crucial in tumorigenesis. Ferroptosis is characterized by iron-dependent oxidative destruction of cellular membranes following the antioxidant system's failure. However, it is unknown whether ferroptosis-related genes (FRGs) are associated with colon adenocarcinoma (COAD) metastasis, immune cell infiltration, and oxidative stress in COAD. The current study concentrated on FRGs expression in colon cancer metastasis, their relationship to immune cell infiltration (ICI), and potential pathological pathways in COAD. Methods and Results: Clinical information and mRNA expression patterns for patients with COAD metastasis were obtained from the public TCGA database. Patients with low mRNA levels showed good overall survival than patients with high mRNA levels. The genomic-clinicopathologic nomogram was subsequently created by combining risk score and clinicopathological features. Absolute Shrinkage and Selection Operator have shown a 4 gene signature that can stratify cancer patients into high-risk versus low-risk. These four FRGs were found to be significantly linked to the overall survival of COAD patients and predicted high risk score. Next, age, stage, and PTNM were combined in univariate and multivariate cox regression models to perform a filtering procedure. The receiver operating characteristic (ROC) and calibration curves indicated that constructed signature model exhibited high prediction accuracy and clinical relevance in COAD. ARID3A showed a strong negative correlation with a wide range of immune tumour-infiltrating cells in COAD microenvironment. According to the single sample gene set enrichment analysis (ssGSEA) results, FRGs are involved in variety of pathological pathways including PI3K-AKT-mTOR pathway, reactive oxygen species (ROS) pathway, response to hypoxia pathway, and other inflammation related pathways. Moreover, dysregulation of FRGs in COAD patients showed a significance correlation with wide range of miRNAs and transcription factors (TFs). Conclusion: We identified new diagnostic biomarkers and established prognostic models for ferroptosis related programmed cell death in COAD metastasis. FRGs may improve tumor cell survival by activating the TGFB pathway, which can stimulate ROS production, accelerates ECM breakdown, and promote tumor progression and invasion. Genes implicated in ferroptosis, as revealed by the Kaplan Meier and a genomic-clinicopathologic nomogram, are potential therapeutic targets and prognosis indications for metastasis COAD patients.

S2856 Poke the Bear and Get the Claws: Life-Threatening Bleeding by Hepatic Artery Infusion Pump Fistula Managed by Over the Scope Clip Closure

Introduction: Hepatic artery infusion (HAI) pumps may be used for regional delivery of chemotherapy for treatment of colorectal cancer liver metastases. Complications are rare, but can include arterial thrombus and catheter dislocation. We present a case of duodenal fistula associated with hepatic artery infusion pump and subsequent closure with over the scope clip. Case Description/Methods: We present the case of a 57-year-old male with stage IV colon adenocarcinoma and liver metastasis who underwent placement of hepatic artery infusion (HAI) pump for local chemotherapy. 6 months later, he presented with 3 days of melena and fatigue with vitals demonstrating heart rate 129 bpm and blood pressure was 111/69 mmHg. Notably, hemoglobin was 9.1 g/dL, down from a baseline of 14.4 g/dL. He was admitted to the surgical oncology service and gastroenterology was consulted for suspected upper GI bleed. Esophagogastroduodenoscopy (EGD) performed the day after admission revealed suspected fistula in the duodenal bulb. Bleeding resolved with proton pump inhibitor therapy alone with plan for outpatient repeat endoscopy. 1 month later the patient presented with anemia, melena and acute blood loss. Repeat EGD demonstrated a bleeding duodenal bulb lesion and hemostasis was achieved by placement of a 12/6t over the scope clip placement. Subsequent CTA scan identified the hepatic artery infusion pump tip adjacent to over the scope clip in the proximal duodenum with no extravasation suggesting resolution of bleeding after clip placement. (Figure) Discussion: We present a rare case of duodenal bleeding due to hepatic artery infusion catheter tip dislocation. A large single center experience of 544 patients over a 15-year period demonstrated the most common complications from HAI to include arterial thrombosis (6%), catheter occlusion/dislodgement (6%) and extrahepatic perfusion (3%)1. Furthermore, literature search for cases from 1975-2022 reveals fewer than 10 cases with this bleeding complication. In this case we demonstrate the successful use of an OTSC to manage bleeding associated from the fistula created by the infusion pump catheter between hepatic artery and duodenal bulb.Figure 1.: A: Index endoscopy showing fistula in the bulb of the duodenum. B: Subsequent endoscopy with bleeding fistula. C: Fistula closure and successful hemostasis with over the scope clip. D: CT scan showing clip with close approximation to the hepatic artery infusion catheter tip.

Proliferative activity of cancer stem cells in the prognosis of hematogenous metastasis of colon adenocarcinoma

The search for prognostic markers to determine the risk of dissemination and metastasis of colon adenocarcinoma is one of the most difficult and actual problems of modern oncomorphology.The aim of this work was to determine the possibility of using indicators of the proliferative activity of cancer stem cells in the prediction of hematogenous metastasis of colon adenocarcinoma. In this work the surgical material from 32 radically operated patients of different ages suffering from a localized colon adenocarcinoma was explored, and relapse-free survival was assessed. A comparative analysis of various components of the tumor differon, including proliferating stem cells and their relationship with the formation of relapse was carried out.An index of stem cell proliferation was proposed to assess the influence of stem cell activity on the biological behavior of tumor. The best rates of relapse-free survival were found in the group of patients with low value of the index of stem cell proliferation compared with patients which index took on high values, which is more typical for elderly and old patients. With a similar comparison of other indicators of tumor differon, including the percentage of ALDH1 and Ki-67-positive cells, as well as cells with the ALDH1+Ki-67+immenophenotype relative to the total tumor differon, no significant relationship with relapse-free survival was found. These results may indicate a high role of ALDH1+ cell proliferation in tumor dissemination, especially in elderly and senile patients, and a lesser influence of both the proliferative activity of Ki-67 and the general population of stem cells on the formation of distant metastases.

Six Genes Associated with Lymphatic Metastasis in Colon Adenocarcinoma Linked to Prognostic Value and Tumor Immune Cell Infiltration.

Objective The aim of the study is to explore the relationship between lymphatic metastasis genes, prognosis, and immune cell infiltration in patients with colon cancer. Methods Based on the Cancer Genome Atlas Program (TCGA) database, differentially expressed genes and prognostic genes related to colon adenocarcinoma (COAD) lymphatic metastasis were screened and intersected. We used lasso and univariate Cox regression analysis to screen core genes and establish a preliminary prediction model. GO and KEGG enrichment analysis was used for lymphatic metastasis-related genes, and single GSEA was used for the final screening results. Finally, we evaluated the relationship between identified genes and immune cell infiltration. Results A total of 1727 genes were differentially expressed between COAD patients with TNM stages of N0 and N1. After further screening, six core genes (RNU4-2, ZNF556, RNVU1-15, NSA2P6, RN7SL767P, and RN7SL473P) were obtained, and a preliminary prediction model was established, in which ZNF556 was a risk factor, and the rest were protective factors. Single GSEA showed that pathways such as systemic lupus erythematosus might play an important role in the initial lymphatic metastasis of COAD. GO and KEGG enrichment analysis of 1727 genes supported this result. Immune infiltration analysis showed that six genes were significantly correlated with T cell and NK cell families. Conclusion Six core genes may affect COAD initial lymphatic metastasis through the systemic lupus erythematosus pathway and immune cell infiltration.

Identification of Necroptosis-Related miRNA Signature as a Potential Predictive Biomarker for Prognosis and Immune Status in Colon Adenocarcinoma.

Objective Increasing studies suggest that necroptosis is correlated with tumor progression. And aberrant microRNA (miRNA) expression plays a vital role in various tumors. Thus, we are committed to exploring a necroptosis-associated miRNA signature to serve as a prognostic biomarker in colon adenocarcinoma (COAD). Data Sources and Methods. In the current study, The Cancer Genome Atlas (TCGA) database was used to download the miRNA and mRNA expression profiles and clinical information of samples. All patients were stochastically assigned to TCGA-train and TCGA-test clusters. Subsequently, we established a prognostic signature comprised of necroptosis-related miRNAs (NR-mis) via LASSO-Cox regression and then developed a nomogram signature composed of the prognostic signature and clinical factors. Corresponding prognostic values were evaluated. Functional analysis, tumor microenvironment (TME), and chemosensitivity of risk subgroups were also identified. Results The prognostic signature based on miR-141-3p, miR-148a-3p, miR-16-5p, and miR-200a-5p was closely associated with overall survival (OS) of samples and tumor metastasis in COAD. The Area Under Curve (AUC) was 0.605, 0.721, and 0.752 in TCGA-train cluster , 0.661, 0.613, and 0.695 in the TCGA-test cluster at 1, 3, and 5 years, respectively. The C-index for nomogram signature was 0.754. Functional analysis showed the remarkable enrichment of the signature-dependent miRNAs in tumor progression and immune response. And two risk subgroups were correlated with the distinct immune infiltration and immune checkpoints. In addition, the high-risk subgroup is more sensitive to cisplatin, doxorubicin, etoposide, and gemcitabine. Conclusions Necroptosis-related miRNAs play a crucial role in the prognosis, metastasis, immune status, and drug sensitivity in COAD.

An integrated approach to understand fluid shear stress-driven and reactive oxygen species-mediated metastasis of colon adenocarcinoma through mRNA-miRNA-lncRNA-circRNA networks.

Development of colon adenocarcinoma (COAD) metastasis involves several mediators including fluid shear stress (FSS), intracellular ROS levels, and non-coding RNAs. In our present study, we identified and investigated the role of regulatory non-coding RNA molecules specifically involved in COAD metastasis and their association with FSS and ROS. Interactions between the mRNAs associated with FSS and ROS, the corresponding microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in COAD metastasis were used to generate the mRNA-miRNA-lncRNA-circRNA network. Experimental validation of the identified RNA hubs using quantitative real-time PCR demonstrated a direct effect of the FSS on their expression levels in cancer cells. FSS resulted in the downregulation of HMGA1 and RAN, as well as the upregulation of HSP90AA1, PMAIP1 and BIRC5. Application of shear stress also led to downregulation of hsa-miR-26b-5p and hsa-miR-34a-5p levels in HCT116 cells. Further, functional enrichment and survival analysis of the significant miRNAs, as well as the OncoPrint and the survival analyses of the selected mRNAs were performed. Subsequently, their functional role was also corroborated with existing literature. Ten significant miRNA hubs were identified, out of which hsa-miR-17-5p and hsa-miR-20a-5p were found to interact with lncRNA (CCAT2) while hsa-miR-335 was found to interact with four circRNAs. Fifteen significant miRNAs were identified in 10 different modules suggesting their importance in FSS and ROS-mediated COAD metastasis. Finally, 10 miRNAs and 3 mRNAs associated with FSS and/or ROS were identified as significant overall survival markers; 33 mRNAs were also identified as metastasis-free survival markers whereas 15 mRNAs showed > 10% gene alterations in TCGA-COAD data and may serve as promising therapeutic biomarkers in the COAD metastasis.

Yiqi Jianpi Huayu Jiedu Decoction Inhibits Metastasis of Colon Adenocarcinoma by Reversing Hsa-miR-374a-3p/Wnt3/β-Catenin-Mediated Epithelial-Mesenchymal Transition and Cellular Plasticity.

Colon adenocarcinoma (COAD) accounts for 95% of colon cancer cases, with the 5-year survival rate significantly affected by local or distant metastases. Yiqi Jianpi Huayu Jiedu decoction (YJHJD), based on the theory of “nourish qi, invigorate the spleen, remove blood stasis, and detoxify”, has long been applied and shown to be remarkable in the prevention and treatment of gastrointestinal tumors. However, the underlying therapeutic mechanisms of YJHJD have not been fully elucidated. Herein, we first confirmed hsa-miR-374a-3p as a tumor suppressor based on its lower expression in the plasma of patients with COAD with liver metastasis and association with more advanced local progression. We also verified WNT3 as a potential target of hsa-miR-374a-3p and observed its increased expression in COAD tissues. Furthermore, we showed that the hsa-miR-374a-3p/Wnt3/β-catenin axis was responsible for epithelial–mesenchymal transition (EMT) and cellular plasticity in COAD, as well as poorer patient prognosis. Our results showed that YJHJD inhibited motility and colony potential in vitro, as well as liver metastasis of COAD in vivo. Moreover, YJHJD induced a reversal of EMT and cellular plasticity-related molecular expression, increased hsa-miR-374a-3p, and decreased Wnt3 and β-catenin levels. In addition, silencing of hsa-miR-374a-3p weakened YJHJD inhibition, whereas the β-catenin inhibitor XAV939 partially repaired it. Taken together, these results demonstrated that YJHJD suppressed the EMT and cellular plasticity of COAD by regulating hsa-miR-374a-3p/Wnt3/β-catenin signaling.

HDAC5, negatively regulated by miR-148a-3p, promotes colon cancer cell migration.

Histone deacetylases (HDACs) are involved in many processes including tumor cell growth and proliferation and regulation of gene expression. To clarify the role of class IIa HDACs in the metastasis of colon adenocarcinoma, we used the class IIa HDAC inhibitor TMP269 and found that it effectively inhibited the migration ability of colon adenocarcinoma cells. Next, we silenced the member of class IIa HDACs and confirmed that the migratory ability of colon adenocarcinoma cells was significantly inhibited by silencing HDAC5 or HDAC7. HDAC5 plays a variety of roles in human cancers. Here, we examined the role of HDAC5 in colon adenocarcinoma. The results indicated that HDAC5 was highly expressed in tumor tissues and negatively correlated with the expression of miR‐148a‐3p. Moreover, the expression of HDAC5 was correlated with tumor progression. HDAC5 markedly increased the invasion and migration of cancer cells in vitro, an effect that could be inhibited by overexpression of miR‐148a‐3p. Following an intraperitoneal injection of colon adenocarcinoma cells in athymic nude mice, HDAC5 promoted tumor implant. Together, these findings showed that HDAC5 overexpression in colon adenocarcinoma is consistent with tumor progression and tumor cell migration and the impact of HDAC5 overexpression is reduced by miR‐148a‐3p.

The Invasion and Metastasis of Colon Adenocarcinoma (COAD) Induced by SALL4

Objective The development and progression of many cancers may be related to SALL4, the role and molecular mechanism of which are unclear in colon adenocarcinoma (COAD). Methods The SALL4 expression in adjacent normal mucosa tissues and carcinoma tissues of patients with COAD was detected through bioinformatic analysis based on TCGA database and immunohistochemistry. Single-cell analysis showed that the expression of SALL4 in normal tissue was noticeably low. GSEA analysis suggested that the SALL4 upregulated the GO and pathway of growth and cancer development and downregulated metabolization pathway. The relationship between lymph node metastasis, histological grading, clinical staging, and the expression of SALL4 in carcinoma tissues was analyzed. The upregulated or downregulated SALL4 expression of COAD cell lines was established. The influence of SALL4 on COAD cells invasion and proliferation was detected using plate cloning assay and Transwell. The expressions of EMT-related proteins E-cadherin, N-cadherin, vimentin, and Twist were detected by Western blot. The EMT phenotype was analyzed by immunofluorescence. Results The study confirmed that the expression of SALL4 was upregulated in COAD and positively correlated with the degree of tumor differentiation, tumor staging, and metastasis. The overexpression of SALL4 was related to a poor prognosis, promoted the invasion and proliferation of colorectal cancer cells, and accelerated the occurrence of EMT, which was characterized by upregulation of Twist, vimentin, and N-cadherin expressions and downregulation of E-cadherin. The immunofluorescence staining confirmed the EMT phenotype. On the contrary, knocking out SALL4 gene reversed EMT, weakened cell proliferation and invasion, inhibited upregulation of Twist, vimentin, and N-cadherin expressions and downregulation of E-cadherin. Conclusion To sum up, TNM grading, histological grading, and lymphatic metastasis were significantly correlated with SALL4 in tumor tissues. SALL4 played a vital role in tumor proliferation, invasion, and tumor EMT and may be a novel target for COAD.

Robot-Assisted Right Colectomy with Sequential Wedge Resection of Segments 4 and 5 of The Liver and Cholecystectomy for Colon Cancer with Metastasis to The Liver

The liver is the most common place for colon adenocarcinoma metastasis because of portal circulation. The surgical intervention for patients with colon adenocarcinoma with synchronous metastasis to the liver has been debated. Studies have shown that the simultaneous resection of a colorectal adenocarcinoma with a liver metastasis has similar outcomes compared to the traditional staged approach when looking at morbidity, mortality, and long-term oncologic effects. There has also been a shift to less invasive procedures when performing abdominal surgery. However, the laparoscopic method that has increasingly been used for the simultaneous procedure is technically challenging and therefore not widely adopted. The technical limitations hindering the simultaneous method could be overcome by utilizing a robotic approach. The aim of this report is to demonstrate the effectiveness of a robotic approach for colon adenocarcinoma with synchronous liver metastases.

GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma.

Glypican-2 (GPC2) has been reported to promote tumor progression through metabolic pathways. However, the role of GPC2 in colon adenocarcinoma (COAD) remains to be further investigated. This study was designed to evaluate the role of GPC2 in COAD. Based on patients with complete clinical information and GPC2 expression from the Cancer Genome Atlas-COAD database, we found that GPC2 mRNA was highly expressed in COAD tissues, which was associated with poor prognosis and tumornode-metastasis (TNM) stage. The predicted survival probability based on GPC2 mRNA expression and TNM stage was in good agreement with the observed survival probability. Furthermore, the genes coexpressed with GPC2 in COAD tissues were significantly enriched in basal cell carcinoma, Notch signaling pathway, and Hedgehog signaling pathway. After GPC2 was decreased through transfecting short hairpin RNA of GPC2 into HCT-8 and SW620 cells, cell cycle was arrested in G0/G1 phase, proliferation was decreased, apoptosis was increased, and migration and invasion were repressed. In conclusion, decreasing GPC2 significantly inhibited proliferation, migration, and invasion, and enhanced apoptosis, which implied that GPC2 can be considered a promising therapeutic target of COAD in the future.