SIRT4 is the molecular switch mediating cellular proliferation in colorectal cancer through GLS mediated activation of AKT/GSK3β/Cyclin D1 pathway

2020 ◽  
Author(s):  
Ying Cui ◽  
Yibing Bai ◽  
Jiani Yang ◽  
Yuanfei Yao ◽  
Chunhui Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Colorectal Cancer Patient ◽  
Migration And Invasion ◽  
In Vivo Models ◽  
Invasion And Migration ◽  
Interactome Network

Abstract Mitochondria-localized sirtuin 4 (SIRT4) is associated with malignant phenotypes in colorectal cancer. However, the molecular mechanisms that drive SIRT4-mediated carcinogenesis are unclear. Initially, we confirmed expression of SIRT4 in colorectal cancer through public database and in colorectal cancer patient tissues using quantitative real-time reverse transcription PCR. We established HCT116 colorectal cells that overexpressed SIRT4 and HT29 cells were transfected with plasmids bearing a small interfering RNA siRNA construct to silence SIRT4. Assays to determine the malignant phenotypes (proliferation, invasion and migration) were performed. Xenograft in-vivo models were also constructed. A protein interactome network was built using differentially expressed proteins identified using the liquid chromatography/tandem mass spectrophotometry, the findings of which were confirmed using coimmunoprecipitation, western blotting, and phenotype rescue experiments. Decreased SIRT4 expression was associated with malignant phenotypes in vitro and in vivo. The ribosomal biogenesis pathway was enriched in the interactome network. SIRT4 suppression activated glutaminase, thereby initiating AKT activation. Our research provided novel insights into the molecular mechanisms underlying colorectal cancer, and identified that SIRT4 exerts its antitumor activity in colorectal cancer possibly dependent on glutaminase to inhibit proliferation, migration, and invasion via the AKT/GSK3β/CyclinD1 pathway.

scholarly journals lncRNA NORAD Contributes to Colorectal Cancer Progression by Inhibition of miR-202-5p

2018 ◽  
Vol 26 (9) ◽  
pp. 1411-1418 ◽  
Author(s):  
Jie Zhang ◽  
Xiao-Yan Li ◽  
Ping Hu ◽  
Yuan-Sheng Ding
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Cancer Metastasis ◽  
Cellular Proliferation ◽  
Inhibitory Effect ◽  
Migration And Invasion ◽  
Competing Endogenous Rna

Previous study indicates that long noncoding RNA NORAD could serve as a competing endogenous RNA to pancreatic cancer metastasis. However, its role in colorectal cancer (CRC) needs to be investigated. In the present study, we found that the expression of NORAD was significantly upregulated in CRC tissues. Furthermore, the expression of NORAD was positively related with CRC metastasis and patients’ poor prognosis. Knockdown of NORAD markedly inhibited CRC cell proliferation, migration, and invasion but induced cell apoptosis in vitro. In vivo experiments also indicated an inhibitory effect of NORAD on tumor growth. Mechanistically, we found that NORAD served as a competing endogenous RNA for miR-202-5p. We found that there was an inverse relationship between the expression of NORAD and miR-202-5p in CRC tissues. Moreover, overexpression of miR-202-5p in SW480 and HCT116 cells significantly inhibited cellular proliferation, migration, and invasion. Taken together, our study demonstrated that the NORAD/miR-202-5p axis plays a pivotal function on CRC progression.

scholarly journals MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 758
Author(s):  
Dan Luo ◽  
Wei Ge
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
The Cancer Genome Atlas ◽  
Mobility Shift ◽  
Migration Ability ◽  
Invasion And Migration ◽  
Distant Organ Metastasis

Background: Recurrence and distant organ metastasis is a major cause of death in colorectal cancer (CRC); however, the underlying molecular mechanisms regulating this phenomenon are poorly understood. MeCP2 is a key epigenetic regulator and is amplified in many types of cancer. Its role in CRC and the molecular mechanisms underlying its action remain unknown. Methods: We used western blot and immunohistochemistry to detect MeCP2 expression in CRC tissues, and then investigated its biological functions in vitro and in vivo. Chromatin immunoprecipitation, co-immunoprecipitation, and electrophoretic mobility shift assays were used to detect the associations among MeCP2 (Methyl-CpG binding protein 2), SPI1 (Spi-1 Proto-Oncogene), and ZEB1 (Zinc Finger E-Box Binding Homeobox 1). Results: Using the Cancer Genome Atlas and Oncomine databases, we found MeCP2 expression was upregulated in CRC tissues and this upregulation was related to poor prognosis. Meanwhile, MeCP2 depletion (KO/KD) in CRC cells significantly inhibited stem cell frequency, and invasion and migration ability in vitro, and suppressed CRC metastasis in vivo. Mechanistically, we show MeCP2 binds to the transcription factor SPI1, and aids its recruitment to the ZEB1 promoter. SPI1 then facilitates ZEB1 expression at the transcription level. In turn, ZEB1 induces the expression of MMP14, CD133, and SOX2, thereby maintaining CRC stemness and metastasis. Conclusions: MeCP2 is a novel regulator of CRC metastasis. MeCP2 suppression may be a promising therapeutic strategy in CRC.

scholarly journals Estrogen Activation by Steroid Sulfatase Increases Colorectal Cancer Proliferation via GPER

2017 ◽  
Vol 102 (12) ◽  
pp. 4435-4447 ◽  
Author(s):  
Lorna C Gilligan ◽  
Habibur P Rahman ◽  
Anne-Marie Hewitt ◽  
Alice J Sitch ◽  
Ali Gondal ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Tissue Growth ◽  
Estrogen Metabolism ◽  
Data Set ◽  
In Vivo Models ◽  
Metabolism Enzymes ◽  
Estradiol Synthesis

Abstract Context Estrogens affect the incidence and progression of colorectal cancer (CRC), although the precise molecular mechanisms remain ill-defined. Objective The present study investigated prereceptor estrogen metabolism through steroid sulphatase (STS) and 17β-hydroxysteroid dehydrogenase activity and subsequent nongenomic estrogen signaling in human CRC tissue, in The Cancer Genome Atlas colon adenocarcinoma data set, and in in vitro and in vivo CRC models. We aimed to define and therapeutically target pathways through which estrogens alter CRC proliferation and progression. Design, Setting, Patients, and Interventions Human CRC samples with normal tissue-matched controls were collected from postmenopausal female and age-matched male patients. Estrogen metabolism enzymes and nongenomic downstream signaling pathways were determined. CRC cell lines were transfected with STS and cultured for in vitro and in vivo analysis. Estrogen metabolism was determined using an ultra-performance liquid chromatography–tandem mass spectrometry method. Primary Outcome Measure The proliferative effects of estrogen metabolism were evaluated using 5-bromo-2′-deoxyuridine assays and CRC mouse xenograft studies. Results Human CRC exhibits dysregulated estrogen metabolism, favoring estradiol synthesis. The activity of STS, the fundamental enzyme that activates conjugated estrogens, is significantly (P < 0.001) elevated in human CRC compared with matched controls. STS overexpression accelerates CRC proliferation in in vitro and in vivo models, with STS inhibition an effective treatment. We defined a G-protein–coupled estrogen receptor (GPER) proproliferative pathway potentially through increased expression of connective tissue growth factor in CRC. Conclusion Human CRC favors estradiol synthesis to augment proliferation via GPER stimulation. Further research is required regarding whether estrogen replacement therapy should be used with caution in patients at high risk of developing CRC.

scholarly journals LOXL1 modulates the malignant progression of colorectal cancer by inhibiting the transcriptional activity of YAP

2020 ◽  
Author(s):  
Lin Hu ◽  
Jing Wang ◽  
Yunliang Wang ◽  
Linpeng Wu ◽  
Chao Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Colony Formation ◽  
Transcriptional Activity ◽  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Migration And Invasion

Abstract Background: LOX-like 1 (LOXL1) is a lysyl oxidase, and emerging evidence has revealed its effect on malignant cancer progression. However, its role in colorectal cancer (CRC) and the underlying molecular mechanisms have not yet been elucidated. Methods: LOXL1 expression in colorectal cancer was detected by immunohistochemistry, western blotting and real-time PCR. In vitro , colony formation, wound healing, migration and invasion assays were performed to investigate the effects of LOXL1 on cell proliferation, migration and invasion. In vivo , metastasis models and mouse xenografts were used to assess tumorigenicity and metastasis ability. Molecular biology experiments were utilized to reveal the underlying mechanisms by which LOXL1 modulates the Hippo pathway. Results: LOXL1 was highly expressed in normal colon tissues compared with cancer tissues. In vitro, silencing LOXL1 in CRC cell lines dramatically enhanced migration, invasion, and colony formation, while overexpression of LOXL1 exerted the opposite effects. The results of the in vivo experiments demonstrated that the overexpression of LOXL1 in CRC cell lines drastically inhibited metastatic progression and tumour growth. Mechanistically, LOXL1 inhibited the transcriptional activity of Yes-associated protein (YAP) by interacting with MST1/2 and increasing the phosphorylation of MST1/2. Conclusions: LOXL1 may function as an important tumour suppressor in regulating tumour growth, invasion and metastasis via negative regulation of YAP activity.

scholarly journals Hsa_circ_0026416 promotes proliferation and migration in colorectal cancer via miR-346/NFIB axis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yahang Liang ◽  
Jingbo Shi ◽  
Qingsi He ◽  
Guorui Sun ◽  
Lei Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Potential Biomarker ◽  
Mouse Xenograft Model

Abstract Background Colorectal cancer (CRC) is one of the most common cancers worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNAs, have been confirmed to be key regulators of many diseases. With many scholars devoted to studying the biological function and mechanism of circRNAs, their mysterious veil is gradually being revealed. In our research, we explored a new circRNA, hsa_circ_0026416, which was identified as upregulated in CRC with the largest fold change (logFC = 3.70) of the evaluated circRNAs via analysing expression profiling data by high throughput sequencing of members of the GEO dataset (GSE77661) to explore the molecular mechanisms of CRC. Methods qRT-PCR and western blot analysis were utilized to assess the expression of hsa_circ_0026416, miR-346 and Nuclear Factor I/B (NFIB). CCK-8 and transwell assays were utilized to examine cell proliferation, migration and invasion in vitro, respectively. A luciferase reporter assay was used to verify the combination of hsa_circ_0026416, miR-346 and NFIB. A nude mouse xenograft model was also utilized to determine the role of hsa_circ_0026416 in CRC cell growth in vivo. Results Hsa_circ_0026416 was markedly upregulated in CRC patient tissues and plasma and was a poor prognosis in CRC patients. In addition, the area under the curve (AUC) of hsa_circ_0026416 (0.767) was greater than the AUC of CEA (0.670), CA19-9 (0.592) and CA72-4 (0.575). Functionally, hsa_circ_0026416 promotes cell proliferation, migration and invasion both in vitro and in vivo. Mechanistically, hsa_circ_0026416 may function as a ceRNA via competitively absorbing miR-346 to upregulate the expression of NFIB. Conclusions In summary, our findings demonstrate that hsa_circ_0026416 is an oncogene in CRC. Hsa_circ_0026416 promotes the progression of CRC via the miR-346/NFIB axis and may represent a potential biomarker for diagnosis and therapy in CRC.

scholarly journals LOXL1 modulates the malignant progression of colorectal cancer by inhibiting the transcriptional activity of YAP

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Lin Hu ◽  
Jing Wang ◽  
Yunliang Wang ◽  
Linpeng Wu ◽  
Chao Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Colony Formation ◽  
Transcriptional Activity ◽  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Migration And Invasion

Abstract Background LOX-like 1 (LOXL1) is a lysyl oxidase, and emerging evidence has revealed its effect on malignant cancer progression. However, its role in colorectal cancer (CRC) and the underlying molecular mechanisms have not yet been elucidated. Methods LOXL1 expression in colorectal cancer was detected by immunohistochemistry, western blotting and real-time PCR. In vitro, colony formation, wound healing, migration and invasion assays were performed to investigate the effects of LOXL1 on cell proliferation, migration and invasion. In vivo, metastasis models and mouse xenografts were used to assess tumorigenicity and metastasis ability. Molecular biology experiments were utilized to reveal the underlying mechanisms by which LOXL1 modulates the Hippo pathway. Results LOXL1 was highly expressed in normal colon tissues compared with cancer tissues. In vitro, silencing LOXL1 in CRC cell lines dramatically enhanced migration, invasion, and colony formation, while overexpression of LOXL1 exerted the opposite effects. The results of the in vivo experiments demonstrated that the overexpression of LOXL1 in CRC cell lines drastically inhibited metastatic progression and tumour growth. Mechanistically, LOXL1 inhibited the transcriptional activity of Yes-associated protein (YAP) by interacting with MST1/2 and increasing the phosphorylation of MST1/2. Conclusions LOXL1 may function as an important tumour suppressor in regulating tumour growth, invasion and metastasis via negative regulation of YAP activity. Graphical abstract

scholarly journals LOXL1 modulates the malignant progression of colorectal cancer by inhibiting the transcriptional activity of YAP

2020 ◽  
Author(s):  
Lin Hu ◽  
Jing Wang ◽  
Yunliang Wang ◽  
Linpeng Wu ◽  
Chao Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Colony Formation ◽  
Transcriptional Activity ◽  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Malignant Progression ◽  
Migration And Invasion

Abstract Background LOX-like 1 (LOXL1), as a lysyl oxidase, emerging evidences revealed the effect in cancer malignant progression. However, its role in colorectal cancer (CRC) and the underlying molecular mechanisms have not yet been elucidated. Methods LOXL1 expression in colorectal cancer was detected by immunohistochemistry, western blot and real-time PCR. In vitro , colony formation assay, wound healing assay, migration and invasion experiment were performed to investigate the effects of LOXL1 in cell proliferation, migration and invasion, respectively. In vivo , metastasis models and mouse xenograft were used to determine tumorigenicity and metastasis ability. Molecular biology experiments were utilized to reveal the underlying mechanisms of LOXL1 modulating Hippo pathway. Results LOXL1 is highly expressed in normal colon tissues compared with cancer tissues. In vitro, Silencing LOXL1 in CRC cell lines dramatically enhanced migration, invasion, and colony formation, while overexpression of LOXL1 manifested the opposite effects. Results of the in vivo experiments demonstrated that the enforced expression of LOXL1 in CRC cell lines had drastically inhibited the progression of metastasis and tumour growth. Mechanistically, LOXL1 inhibited the transcriptional activity of Yes-associated protein (YAP) was through interaction with MST1/2 and increasing the phosphorylation of MST1/2. Conclusions LOXL1 may function as an important tumour suppressor in regulating tumour growth, invasion and metastasis via negative regulating of YAP activity.

scholarly journals Metformin Inhibits the Development and Metastasis of Colorectal Cancer

2021 ◽  
Author(s):  
Kiyoaki Sugiura ◽  
Koji Okabayashi ◽  
Ryo Seishima ◽  
Takashi Ishida ◽  
Kohei Shigeta ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Liver Tumors ◽  
Immunohistochemical Analysis ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Invasion And Migration ◽  
Anti Cancer

Abstract BackgroundMetformin is a commonly used drug for the treatment of diabetes. Accumulating evidence suggests that it exerts anti-cancer effects in many cancers, including colorectal cancer. However, the underlying molecular mechanisms of colorectal cancer metastasis remain unclear.MethodsColorectal cancer cell lines were treated with metformin, and cell proliferation, invasion, and migration were analyzed in vitro. The relationship between metformin and the AMPK–mTOR axis was assessed by western blot analysis and transfection with small interfering RNA. A colorectal cancer xenograft mouse model was used to observe the effects of metformin on liver metastasis. Immunohistochemical analysis was performed on liver metastatic tumors.ResultsIn in vitro experiments, metformin significantly inhibited the proliferation, migration, and invasion only in HCT116 and SW837 cells, but not in HCT8 and Lovo cells. Only in HCT116 and SW837, a change in AMPK–mTOR expression was observed in a dose-dependent manner. In colorectal cancer xenograft mice, the liver metastatic rate (10% vs. 50%, p = 0.05) and the number of liver metastatic nodules (0.1/body vs. 1.2/body, p = 0.04) were significantly lower in the metformin group. Tumor proliferation and EMT were decreased and apoptosis was promoted only in metastatic liver tumors of mice treated with metformin.ConclusionThe molecular mechanism of the anti-cancer effects of metformin involves repression of mTOR pathways via AMPK activation. Moreover, the differences in metformin sensitivity depend on the response of the AMPK–mTOR pathway to metformin. Our study provides a theoretical basis for the anti-metastatic treatment of colorectal cancer using metformin.

scholarly journals NFATc1 Promotes Epithelial-Mesenchymal Transition and Facilitates Colorectal Cancer Metastasis by Targeting SNAI1

2020 ◽  
Author(s):  
Tianli Shen ◽  
Chenyang Yue ◽  
Xingjie Wang ◽  
Zijun Wang ◽  
Yunhua Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Activated T Cells ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Clinical Stages

Abstract BackgroundMetastatic recurrence remains a major cause of colorectal cancer (CRC) mortality. In this study, we focused on the role and the potential underlying mechanisms of nuclear factor of activated T cells 1 (NFATc1) in CRC metastasis. MethodsWe examined the expression of NFATc1 in 140 cases of CRC tissues and 35 corresponding adjacent tissues, as well as analyzed the correlation between NFATc1 expression levels and clinical stages. The role of NFATc1 in CRC metastasis and the molecular mechanisms were investigated in both in vitro and in vivo models. ResultsThe results showed that NFATc1 expression was increased in metastatic CRC tissues and positively associated with clinical stages (Stage I vs. Stage II, III or IV) of CRC. Overexpression of NFATc1 promoted CRC cell migration, invasion and epithelial-mesenchymal transition (EMT). Moreover, SNAI1 was verified as the direct transcriptional target of NFATc1 and interacted with Slug to promote EMT. Remarkably, our lung and liver double metastasis mouse model demonstrated that NFATc1 overexpression accelerated CRC metastasis, and treatment with FK506, a calcineurin-NFAT pathway inhibitor, could suppress CRC metastasis in vivo. ConclusionsTaken together, our findings suggest that NFATc1 could transcriptionally activate SNAI1, which in turn could interact with Slug to mediate EMT and to promote CRC metastasis, making NFATc1 a promising target in CRC treatment.

scholarly journals PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Xin-Ke Yin ◽  
Yun-Long Wang ◽  
Fei Wang ◽  
Wei-Xing Feng ◽  
Shao-Mei Bai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Locally Advanced ◽  
Xenograft Model ◽  
Arginine Methylation ◽  
Mass Spectrometry Analysis ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Potential Marker

AbstractArginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.

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