Overexpression of GLUT1 in Colorectal Cancer is Independently Associated with Poor Prognosis

Background To investigate the expression of glucose transporter 1 (GLUT1) in colorectal cancer (CRC) and its relationship to clinicopathological variables. Methods The expression of GLUT1 in 163 primary tumors together with the corresponding normal mucosa, and 36 liver metastases was examined using real-time PCR. Results The mean value of GLUT1 was higher in primary tumors (50.390 ± 68.648) than in the corresponding normal mucosa (20.437 ± 28.703, p<0.0001), while there was no significant difference in GLUT1 expression between CRC and liver metastasis (50.390 ± 68.648 vs 52.277 ± 52.482, p=0.190). In CRCs, GLUT1 expression was higher in poorly differentiated than in well and moderately differentiated tumors (p=0.022), and higher in stage III + IV than in stage I + II tumors (p=0.035). The patients with high-expressed GLUT1 had a worse prognosis than those with low-expressed GLUT1 independently of gender, age, tumor site, stage and differentiation (p=0.026, RR 2.737, 95% CI 1.126–6.651) in stage I-III CRCs. In liver metastasis, GLUT1 expression was higher in larger tumors than in smaller ones (p=0.025). Conclusions Overexpression of GLUT1 in stage I-III CRCs was independently associated with poor prognosis.

Download Full-text

Identifying metastasis-initiating miRNA-target regulations of colorectal cancer from expressional changes in primary tumors

Scientific Reports ◽

10.1038/s41598-020-71868-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jongmin Lee ◽

Hye Kyung Hong ◽

Sheng-Bin Peng ◽

Tae Won Kim ◽

Woo Yong Lee ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Cancer Progression ◽

Cancer Biology ◽

Mirna Target ◽

Target Genes ◽

Expression Profiles ◽

Statistical Significance ◽

Primary Tumors ◽

Significant Difference

Abstract Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

Download Full-text

Glucose Transporter 1 (SLC2A1) and Vascular Endothelial Growth Factor A (VEGFA) Predict Survival After Resection of Colorectal Cancer Liver Metastasis

Annals of Surgery ◽

10.1097/sla.0000000000001109 ◽

2016 ◽

Vol 263 (1) ◽

pp. 138-145 ◽

Cited By ~ 23

Author(s):

Jeroen A. C. M. Goos ◽

Erienne M. V. de Cuba ◽

Veerle M. H. Coupé ◽

Begoña Diosdado ◽

Pien M. Delis-Van Diemen ◽

...

Keyword(s):

Colorectal Cancer ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Liver Metastasis ◽

Glucose Transporter ◽

Vascular Endothelial ◽

Glucose Transporter 1 ◽

Colorectal Cancer Liver Metastasis ◽

Endothelial Growth Factor

Download Full-text

The Interaction of GLUT1 and FOXM1 Leads to a Poor Prognosis in Colorectal Cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200318094618 ◽

2020 ◽

Vol 20 (8) ◽

pp. 941-950 ◽

Cited By ~ 1

Author(s):

Xiao-Yi Kuai ◽

Zhi-Yi Lei ◽

Xiao-Shuang Liu ◽

Xin-Yu Shao

Keyword(s):

Colorectal Cancer ◽

Glucose Metabolism ◽

Poor Prognosis ◽

Glucose Transporter ◽

Underlying Mechanism ◽

Tumor Location ◽

Positive Lymph Node ◽

High Morbidity ◽

Glucose Transporter 1 ◽

Normal Tissues

Background: Colorectal Cancer (CRC) is one of the most common fatal diseases with high morbidity. Alteration of glucose metabolism is one of the hallmarks in the development of CRC. Glucose Transporter 1 (GLUT1) is a key rate-limiting protein in hyperactive glucose metabolism and up-regulated in CRC, however, the underlying mechanism of the altered metabolism in CRC is still unknown. Methods: In this study, immunohistochemical staining was used to evaluate the expression of GLUT1 and FOXM1 in 135 paired CRC and adjacent normal tissues. The association between the expression of GLUT1/FOXM1 and clinicopathological factors was determined and the correlation between GLUT1 and FOXM1 in CRC was investigated. Results: Our results revealed that regardless of tumor location, GLUT1 and FOXM1 were overexpressed in CRC tissues, especially in patients with positive lymph node metastasis and TNM stage III-IV. Furthermore, GLUT1 showed a significantly strong link with FOXM1 in CRC tissue. Conclusions: Overexpression of GLUT1 and FOXM1 may play critical roles in CRC leading to a poor prognosis.

Download Full-text

High Expression of sLex Associated with Poor Survival in Argentinian Colorectal Cancer Patients

The International Journal of Biological Markers ◽

10.5301/jbm.5000060 ◽

2014 ◽

Vol 29 (1) ◽

pp. e30-e39 ◽

Cited By ~ 5

Author(s):

Ariel Zwenger ◽

Martin Rabassa ◽

Sandra Demichelis ◽

Gabriel Grossman ◽

Amada Segal-Eiras ◽

...

Keyword(s):

Colorectal Cancer ◽

Lymph Nodes ◽

Cancer Patients ◽

Normal Mucosa ◽

Poor Survival ◽

Primary Tumors ◽

Metastatic Lymph Nodes ◽

Metastatic Lymph ◽

Colorectal Cancer Patients

Aim Colorectal cancer (CRC) is one of the most prevalent malignancies in Argentina with 11,043 new cases and 6,596 deaths estimated to have occurred in 2008. The present study was developed to clarify the differential expression of MUC1, MUC2, sLex, and sLea in colorectal cancer patients and their relationship with survival and clinical and histological features. Methods Ninety primary tumor samples and 43 metastatic lymph nodes from CRC patients were studied; follow-up was documented. Twenty-six adenoma and 68 histological normal mucosa specimens were analyzed. An immunohistochemical approach was applied and statistical analysis was performed. Results In tumor samples, MUC1, sLea, and sLex were highly expressed (94%, 67%, and 91%, respectively); also, we found a significantly increased expression of the 3 antigens in primary tumors and metastatic lymph nodes compared with normal mucosa and adenomas. MUC2 was expressed in 52% of both normal mucosa and CRC samples; this reactivity significantly decreased in metastatic lymph nodes (p<0.05). A multiple comparison analysis showed that MUC1 and sLex discriminated among 3 groups: normal, adenoma, and CRC tissues. The increase of sLex expression showed an association with recurrence, and survival analysis showed that a high sLex staining was significantly associated with a poor survival. By multivariate analysis MUC1 inmunoreactivity correlated positively and significantly with tumor size, while MUC2 expression showed the opposite correlation. Conclusions The correlation of sLex overexpression in primary tumors and metastatic lymph nodes, the discrimination among the normal, adenoma, and CRC groups based on sLex expression, as well as its association with recurrence and survival, all suggest a prognostic role of sLex in Argentinian CRC patients.

Download Full-text

Perspectives on Immunotherapy of Metastatic Colorectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.659964 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yongjiu Dai ◽

Wenhu Zhao ◽

Lei Yue ◽

Xinzheng Dai ◽

Dawei Rong ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trials ◽

Liver Metastasis ◽

Experimental Design ◽

Poor Prognosis ◽

Response Rate ◽

Traditional Treatment ◽

The Poor ◽

New Thinking ◽

New Treatment

Colorectal cancer, especially liver metastasis, is still a challenge worldwide. Traditional treatment such as surgery, chemotherapy and radiotherapy have been difficult to be further advanced. We need to develop new treatment methods to further improve the poor prognosis of these patients. The emergence of immunotherapy has brought light to mCRC patients, especially those with dMMR. Based on several large trials, some drugs (pembrolizumab, nivolumab) have been approved by US Food and Drug Administration to treat the patients diagnosed with dMMR tumors. However, immunotherapy has reached a bottleneck for other MSS tumors, with low response rate and poor PFS and OS. Therefore, more clinical trials are underway toward mCRC patients, especially those with MSS. This review is intended to summarize the existing clinical trials to illustrate the development of immunotherapy in mCRC patients, and to provide a new thinking for the direction and experimental design of immunotherapy in the future.

Download Full-text

The Effect of High CDC6 Levels on Predicting Poor Prognosis in Colorectal Cancer

Chemotherapy ◽

10.1159/000519913 ◽

2022 ◽

pp. 1-10

Author(s):

Cheng Yang ◽

Na Xie ◽

Zhifei Luo ◽

Xiling Ruan ◽

Yixin Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Protein Expression ◽

Poor Prognosis ◽

Cancer Metastasis ◽

Mrna Level ◽

Normal Mucosa ◽

Tnm Stage ◽

Expression Levels ◽

Normal Tissues

Introduction: We investigated the function of cell division cycle 6 (CDC6) on the prognosis in colorectal carcinoma (CRC). Methods: CDC6 protein expression levels in 121 patients with colorectal cancer and adjacent normal mucosa were detected by immunohistochemistry. Results: Compared to adjacent normal tissues, CDC6 mRNA level was overexpressed in CRC tissues. Moreover, CDC6 protein levels were expressed up to 93.39% (113/121) in CRC tissues in the cell nucleus or cytoplasm. However, there were only 5.79% (7/121) in normal mucosal tissues with nuclear expression. CDC6 expression was significantly correlated with TNM stage and tumor metastasis. The 5-year survival rate was lower in the high CDC6 expression group than the low group. After silencing of CDC6 expression in SW620 cells, cell proliferation was slowed, the tumor clones were decreased, and the cell cycle was arrested in G1 phase. In multivariate analysis, increased CDC6 protein expression levels in colon cancer tissues were associated with cancer metastasis, TNM stage, and patient survival time. Conclusion: CDC6 is highly expressed in CRC, and downregulation of CDC6 can slow the growth of CRC cells in vitro. It is also an independent predictor for poor prognosis and may be a useful biomarker for targeted therapy and prognostic evaluation.

Download Full-text

Effect of Addition of WZB117 as an Inhibitor of Glucose Transporter 1 for Venous Blood Glucose Determination

Laboratory Medicine ◽

10.1093/labmed/lmaa051 ◽

2020 ◽

Author(s):

Lei Zhang ◽

Yaqiong Ran ◽

Yan Zhu ◽

Qianna Zhen

Keyword(s):

Blood Glucose ◽

Glucose Level ◽

Glucose Transporter ◽

Venous Blood ◽

Sugar Transport ◽

Glucose Transporter 1 ◽

Glucose Determination ◽

Glucose Levels ◽

Significant Difference ◽

Blood Glucose Determination

Abstract Objective Sodium fluoride (NaF) has been applied to inhibit glycolysis in venous specimens for decades. However, it has had little effect on the rate of glycolysis in the first 1 to 2 hours, resulting in a decrease of glucose, so a more efficient method is needed. Recently, we discovered that WZB117, a specific Glut1 inhibitor, restricts glycolysis by inhibiting the passive sugar transport of human red blood cells and cancer cells. The purpose of this study was to evaluate the results of intravenous blood glucose determination after the addition of WZB117. Methods Venous specimens from 40 pairs of healthy volunteers were collected for several days and placed in tubes containing NaF plus EDTA-disodium (Na2) without WZB117 (the A group); citric acid, trisodium citrate, and EDTA-Na2 without WZB117 (B group); and NaF plus EDTA-Na2 with WZB117 (C group). The glucose concentration was measured after venipuncture and compared with test tubes treated for 1 hour, 2 hours, and 3 hours before centrifugation. Glucose level was determined by the hexokinase method. The paired t-test was used to examine differences in glucose values at baseline and at different time points. The number of misdiagnoses and the misdiagnosis rate were calculated at 2 diagnostic stages: high risk of diabetes (glucose level of 6.1 mmol/L) and diagnosis of diabetes (glucose level of 7.0 mmol/L). Results Glucose levels decreased by 1.0% at 1 hour and by 2.1% at 3 hours in the C group tubes and simultaneously decreased by 1.7% at 1 hour and by 2.5% at 3 hours in the B group tubes. In contrast, glucose levels decreased by 4.1% at 1 hour and by 6.3% at 3 hours in the A group tubes. There was a statistically significant difference in glucose levels measured in the A group tubes and B group tubes at 1 hour, 2 hours, and 3 hours. The misdiagnosis rate of clinical diagnosis in diabetes was highest in the A group tubes (7.0‰ at 1 hour, 0.1‰ at 3 hours at 7.0 mmol/L point; 14.6‰ at 1 hour, 0.4‰ at 3 hours at 6.1 mmol/L point) and lowest in the C group tubes (2.95‰ at 1 hour, 0‰ at 3 hours at 7.0 mmol/L point; 4.8‰ at 1 hour, 0.1‰ at 3 hours at 6.1 mmol/L point). Conclusion The tube addition of WZB117 is more suitable for minimizing glycolysis and has no effect on glucose levels even if specimens are left uncentrifuged for up to 3 hours.

Download Full-text

The mechanism of the premetastatic niche facilitating colorectal cancer liver metastasis generated from myeloid-derived suppressor cells induced by the S1PR1–STAT3 signaling pathway

Cell Death and Disease ◽

10.1038/s41419-019-1922-5 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 8

Author(s):

Qi Lin ◽

Li Ren ◽

Mi Jian ◽

Pingping Xu ◽

Jun Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

T Cell ◽

Liver Metastasis ◽

Signaling Pathway ◽

Mouse Models ◽

Poor Prognosis ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Premetastatic Niche

Abstract The tumor-derived factors involved in the expansion and accumulation of myeloid-derived suppressor cells (MDSCs) in metastatic dissemination of colorectal cancer (CRC) to the liver has not been studied. Immunohistochemistry was used to detect sphingosine-1-phosphate receptor 1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) in human colorectal tumors. IL-6 and interferon-γ were detected by enzyme-linked immunosorbent assay (ELISA). Tumor growth, invasion, and migration were evaluated by MTT, transwell, and wound healing assays, respectively. Subcutaneous tumor-bearing and CRC liver metastasis (CRLM) nude mouse models were constructed. The percentage of MDSCs was measured using multicolor flow cytometry. Western blot assay was used to evaluate S1PR1 and p-STAT3 expression in MDSCs after separation from the liver and tumor by magnetic antibody. T-cell suppression assay was detected by carboxyfluorescein succinimidyl ester (CFSE). Aberrant co-expressed S1PR1 and p-STAT3 was correlated with metachronous liver metastasis and poor prognosis in CRC. A mutual activation loop between S1PR1 and STAT3 can enhance CRC cell proliferation, migration, and invasion in vitro and in vivo. The expression of p-STAT3 and its downstream proteins can be regulated by S1PR1. p-STAT3 was the dependent signaling pathway of S1PR1 in the promotion of cell growth and liver metastasis in CRC. The level of IL-6 and the associated MDSCs stimulated by the S1PR1–STAT3 correlated with the number of liver metastatic nodes in the CRLM mouse models and patients. Increased CD14+HLA-DR−/low MDSCs from CRLM patients inhibited autologous T-cell proliferation and predict poor prognosis. The S1PR1–STAT3–IL-6–MDSCs axis operates in both tumor cells and MDSCs involved in the promotion of growth and liver metastasis in CRC. MDSCs induced by S1PR1–STAT3 in CRC cells formed the premetastatic niche in the liver can promote organ-specific metastasis.

Download Full-text