Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation
Filipe C. LourençoJune MunroJennifer G. BrownJulia B. CorderoRhoda StefanatosKaren StrathdeeClare OrangeStephan M. FellerOwen J. SansomMarcos VidalGraeme I. MurrayMichael F. Olson
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Abstract:
Objective
Colorectal cancer (CRC) is a major contributor to cancer mortality and morbidity. LIM kinase 2 (LIMK2) promotes tumour cell invasion and metastasis. The objectives of this study were to determine how LIMK2 expression is associated with CRC progression and patient outcome, and to use genetically modified Drosophila and mice to determine how LIMK2 deletion affects gastrointestinal stem cell regulation and tumour development.Design
LIMK2 expression and activity were measured by immunostaining tumours from CRC-prone mice, human CRC cell lines and 650 human tumours. LIMK knockdown in Drosophila or Limk2 deletion in mice allowed for assessment of their contributions to gastrointestinal stem cell homeostasis and tumour development.Results
LIMK2 expression was reduced in intestinal tumours of cancer-prone mice, as well as in human CRC cell lines and tumours. Reduced LIMK2 expression and substrate phosphorylation were associated with shorter patient survival. Genetic analysis in Drosophila midgut and intestinal epithelial cells isolated from genetically modified mice revealed a conserved role for LIMK2 in constraining gastrointestinal stem cell proliferation. Limk2 deletion increased colon tumour size in a colitis-associated colorectal mouse cancer model.Conclusions
This study revealed that LIMK2 expression and activity progressively decrease with advancing stage, and supports the hypothesis that there is selective pressure for reduced LIMK2 expression in CRC to relieve negative constraints imposed upon gastrointestinal stem cells.Although somatic mutations in colorectal cancer are well characterized, little is known about the accumulation of cancer mutations in the normal colon before cancer. Here, we have developed and applied an ultrasensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without colorectal cancer. This testing platform revealed that normal colon from patients with and without colorectal cancer carries mutations in common colorectal cancer genes, but these mutations are more abundant in patients with cancer. Oncogenic KRAS mutations were observed in the normal colon of about one third of patients with colorectal cancer but in none of the patients without colorectal cancer. Patients with colorectal cancer also carried more TP53 mutations than patients without cancer and these mutations were more pathogenic and formed larger clones, especially in patients with early-onset colorectal cancer. Most mutations in the normal colon were different from the driver mutations in tumors, suggesting that the occurrence of independent clones with pathogenic KRAS and TP53 mutations is a common event in the colon of individuals who develop colorectal cancer. These results indicate that somatic evolution contributes to clonal expansions in the normal colon and that this process is enhanced in individuals with cancer, particularly in those with early-onset colorectal cancer.
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Objective To investigate the expression and significance of δ-catenin in colorectal cancer(CRC),and explore the correlation between8-catenin expression and cell proliferation in colorectal cancer.Methods The expressions of 8-catenin and Ki-67 in 120 specimens of colorectal cancer were detected by immunohistochemistry in tissue microassay.The expression of 8-catenin was also determined in 30 paired colorectal cancer and normal colorectum by Western blot.Results Overexpression of 8-catenin was detected in 65.83%(79/120) of the 120 human colorectal cancer tissues,which was significantly higher than that in normal colorectum.The positive expression of 8-catenin was higher in advanced TNM stages(Ⅲ+ Ⅳ)of colorectal cancer(78.05%,32/41),compared to lower stages(Ⅰ+Ⅱ)(59.49%,47/79)(x~2=4.132,P= 0.042).The positive expression of 8-catenin was higher in poor differentiated colorectal cancer(82.14%,23/28),compared to well/moderate differentiated colorectal cancer(60.87%,56/92)(x~2=4-319,P = 0.038).The positive expression of 8-catenin was higher in colorectal cancer with lymph node metastasis(77.05%,47/61),compared to colorectal cancer without lymph node metastasis(54.24%,32/59)(x~2=6-939,P = 0.008).In addition,we also found that the overexpression of 8-catenin was positively correlated with proliferation of colorectal cancer which marked by Ki-67 staining in colorectal cancer(r=0.334,P 0.01).Conclusion 8-catenin overexpression might be involved in the initiation and progression of colorectal cancer.
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Objective To observe the expression of Claudin-2 in colorectal cancer tissues and to explore its relationship with the development and progression of colorectal cancer.Methods Immunohistochemical staining(SP method) was used to detect the expression of Claudin-2 in colorectal cancer tissue,adjacent normal tissue of colorectal cancer and normal tissue and investigate the correlation between expression of Claudin-2 in colorectal cancer tissue and the genesis and development of colorectal cancer.Results The expression of Claudin-2 in colorectal cancer tissues was significantly higher than those in the adjacent tissues of colorectal cancer and normal colorectal tissue(P0.05);besides,the expression of Claudin-2 in the colorectal cancer tissue was correlated with degree of differentiation,Dukes stages of colorectal cancer(P0.05).Conclusion The expression of Claudin-2 in colorectal cancer increases significantly in both positive rate and intensity compared with that in normal tissue.The higher expression of Claudin-2 may play an important role in the genesis and development of colorectal cancer.
Claudin
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Objective To detect the expression and role of PTTG mRNA in human colorectal cancer.Methods The expression of PTTG mRNA was evaluated in 12 normal colorectal tissues,20 colorectal adenoma tissues and 44 colorectal cancer tissues by RT-PCR.Results The expression of PTTG mRNA in colorectal cancer was significantly higher than that in colorectal adenoma and normal colorectal tissues.The PTTG mRNA expression in the Dukes C,D colorectal cancer was higher than that in the Dukes A,B cancer(P0.05).The expression in the colorectal cancer with lymph node metastasis was higher than that in the cancer without lymph node metastasis(P0.05).Conclusion The expression of PTTG mRNA increases in colorectal cancer,and is related with cell differentiation and metastasis.The abnormal expression of PTTG probably participates in genesis and development of colorectal cancers.
Colorectal adenoma
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microRNAs (miRNAs) dysregulation is widely involved in cancer progression and contributed to sustained cell proliferation by directly targeting multiple targets. Therefore, better understanding the underlying mechanism of miRNA in carcinogenesis may improve diagnostic and therapeutic strategies for malignancy. In our study, we found that mir-765 is upregulated in both hepatocellular carcinoma (HCC) cell lines and tissues, compared to human normal liver cell line and adjacent non-cancerous tissues, respectively. Overexpression of mir-765 increased HCC cells proliferation and tumorigenicity, whereas inhibition of mir-765 reverses this effect. Furthermore, we demonstrated that INPP4B as a direct target of mir-765 and ectopic expression of mir-765 repressed INPP4B expression, resulting in upregulation of p-AKT, Cyclin D1, and downregulation of p-FOXO3a, p21 expression in HCC. Strikingly, we found that silencing the expression of INPP4B is the essential biological function of miR-765 during HCC cell proliferation. Collectively, our findings reveal that miR-765 is a potential onco-miR that participates in carcinogenesis of human HCC by suppressing INPP4B expression, and might represent a potential therapeutic target for HCC patients.
Ectopic expression
Cyclin E1
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<div>Abstract<p>Although somatic mutations in colorectal cancer are well characterized, little is known about the accumulation of cancer mutations in the normal colon before cancer. Here, we have developed and applied an ultrasensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without colorectal cancer. This testing platform revealed that normal colon from patients with and without colorectal cancer carries mutations in common colorectal cancer genes, but these mutations are more abundant in patients with cancer. Oncogenic <i>KRAS</i> mutations were observed in the normal colon of about one third of patients with colorectal cancer but in none of the patients without colorectal cancer. Patients with colorectal cancer also carried more <i>TP53</i> mutations than patients without cancer and these mutations were more pathogenic and formed larger clones, especially in patients with early-onset colorectal cancer. Most mutations in the normal colon were different from the driver mutations in tumors, suggesting that the occurrence of independent clones with pathogenic <i>KRAS</i> and <i>TP53</i> mutations is a common event in the colon of individuals who develop colorectal cancer. These results indicate that somatic evolution contributes to clonal expansions in the normal colon and that this process is enhanced in individuals with cancer, particularly in those with early-onset colorectal cancer.</p>Significance:<p>This work suggests prevalent somatic evolution in the normal colon of patients with colorectal cancer, highlighting the potential of using ultrasensitive gene sequencing to predict disease risk.</p></div>
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Abstract Background: Solute carrier family 25 member 24 (SLC25A24) is a member of the mitochondrial solute vector (MSC) protein superfamily. More and more evidence suggested that SLC family members play an extremely important role in cancers. However, the biological function of SLC25A24 in colorectal cancer has not been reported. Methods: TCGA, GEO, UALCAN, Sangebox3.0 and TIDE databases were used to analyze SLC25A24 in colorectal cancer. The expression of SLC25A24 in 83 pairs of colorectal cancer tissues was detected by immunohistochemistry. qRT-PCR, Western blotting and apoptosis assays were used to explore the biological function of SLC25A24 in colorectal cancer. Results: Through analysis of multiple databases, we found that SLC25A24 expression was higher in colorectal cancer than in adjacent normal tissues, and higher expression of SLC25A24 had a better prognosis. This was verified by clinical case analysis. In addition, based on multiple algorithms of immune infiltration, we found that SLC25A24 was significantly associated with immune infiltration in colorectal cancer. SLC25A24 was significantly associated with clinicopathological features in 83 patients with colorectal cancer. Importantly, SLC25A24 knockdown significantly promoted the apoptosis ability of colorectal cancer cells. In addition, we also found that lower expression of SLC25A24 was associated with poor prognosis and low immunotherapy sensitivity in patients with colorectal cancer. Therefore, SLC25A24 might be a biomarker for the treatment of colorectal cancer. Conclusion: In summary, we found that SLC25A24 was higher expression in colorectal cancer than in adjacent normal tissues, and higher expression of SLC25A24 had a better prognosis. Importantly, we found that SLC25A24 inhibited apoptosis of colorectal cancer cells. In addition, SLC25A24 was associated with immune infiltration of colorectal cancer. Patients with lower expression of SLC25A24 were more prone to immune escape, while patients with higher expression of SLC25A24 were more conducive to immunotherapy. These results suggested that SLC25A24 might be a potential therapeutic target for patients with colorectal cancer.
Infiltration (HVAC)
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Abstract Colorectal cancer is a crucial health-threatening problem. In recent years, the treatment of colorectal cancer has continued improved and update. But the prognosis of advanced colorectal cancer is still disappointing. Galecitn-9 is a member of the galectin family which has been verified to have multiple biological regulatory functions. Our team has been studying the clinical application of the galectin family in gastric and colorectal cancer. However, we do not yet unveil the correlation between Galecitn-9 and colorectal cancer. This study aimed to elucidate the expression of Galecitn-9 in colorectal cancer and the effect of Galecitn-9 on colorectal cancer proliferation, migration and invasion.
Clinical Significance
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Abstract Background As a phosphorylated protein, NOLC1 is mainly located in the nucleus and is highly expressed in a variety of tumors, participating in the regulation of cell proliferation and aging. This study further investigated the role of NOLC1 in colorectal cancer tumors, aiming to provide sufficient scientific evidence for the clinical treatment of colorectal cancer. Methods We used TCGA, GEO, TNMplot, GEPIA, and other databases to explore the expression level of NOLC1 in colorectal cancer patients, as well as the correlation between the clinical characteristics of colorectal cancer patients and their expression, and conducted the prognostic analysis. Immunohistofluorescence (IHF) staining verified the analytical results. Subsequently, KEGG and GO enrichment analysis was used to identify the potential molecular mechanism of NOLC1 promoting the occurrence and development of colorectal cancer. The influence of NOLC1 expression on the immune microenvironment of colorectal cancer patients was further investigated using the TIMER database. GDSC database analysis was used to screen out possible anti-colorectal cancer drugs against NOLC1. Finally, we demonstrated the effect of NOLC1 on the activity and migration of colorectal cancer cells by Edu Cell proliferation assay and Wound Healing assay in vitro. Results Our results suggest that NOLC1 is overexpressed in colorectal cancer, and that overexpression of NOLC1 is associated with relevant clinical features. NOLC1, as an independent risk factor affecting the prognosis of colorectal cancer patients, can lead to a poor prognosis of colorectal cancer. In addition, NOLC1 may be associated with MCM10, HELLS, NOC3L, and other genes through participating in Wnt signaling pathways and jointly regulate the occurrence and development of colorectal cancer under the influence of the tumor microenvironment and many other influencing factors. Related to NOLC1: Selumetinib, Imatinib, and targeted drugs such as Lapatinib have potential value in the clinical application of colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells. Conclusions High expression of NOLC1 as an independent prognostic factor for survival in patients with colorectal cancer. NOLC1 enhances the proliferation and migration of colorectal cancer cells. Further studies and clinical trials are needed to confirm the role of NOLC1 in the development and progression of colorectal cancer.
Hematology
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