scholarly journals Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

2019 ◽  
Author(s):  
Qing Liu ◽  
Chaogang Yang ◽  
Shuyi Wang ◽  
Dongdong Shi ◽  
Chen Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Xenograft Model ◽  
Neutralizing Antibody ◽  
Tumor Stroma ◽  
Migration And Invasion ◽  
Tumor Associated Macrophages ◽  
Stat3 Pathway ◽  
M2 Polarization

Abstract Background: Tumor-associated macrophages (TAMs) in the tumor microenvironment influence tumor initiation, invasion and metastasis. Several studies have shown that Wnt5a is mainly expressed in the tumor stroma, especially in TAMs. However, whether Wnt5a regulates the polarization and biological function of TAMs in colorectal cancer (CRC) is incompletely understood. Methods: Immunofluorescence staining was performed to detect CD68 and Wnt5a expression in colorectal tissues from patients (63 CRC specimens VS 20 normal tissues). RT-qPCR, flow cytometry, ELISA and inhibitors were carried out to explore the role of Wnt5a in the polarization of TAMs. Clone formation and transwell assays were performed to determine the effects of Wnt5a–treated macrophages on tumor proliferation, migration and invasion in vitro. Finally, a xenograft model was applied to confirm the effects of Wnt5a+ TAMs on CRC tumorigenesis. Results: We found that high Wnt5a+CD68+/CD68+ TAMs ratio was significantly associated with poor prognosis in CRC patients and Wnt5a+ TAM was an M2-like TAM subtype. Subsequently, we found that Wnt5a induced macrophages to secrete IL-10, which then acted as an autocrine cytokine to induce M2 polarization of these macrophages. IL-10 neutralizing antibody completely reversed the pro-M2 effect of Wnt5a. Mechanistically, the CaKMII-ERK1/2-STAT3 pathway was required for Wnt5a-mediated IL-10 expression in macrophages. Furthermore, Wnt5a-induced M2 macrophages promoted CRC cells proliferation, migration and invasion; knockdown of Wnt5a in TAMs significantly impaired the pro-tumor functions of TAMs. Conclusions: Our data indicate that Wnt5a could induce M2 polarization of TAMs by regulating CaKMII-ERK1/2-STAT3 pathway–mediated IL-10 secretion, ultimately promoting tumor growth and metastasis of CRC.

scholarly journals Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

2020 ◽  
Author(s):  
Qing Liu ◽  
Chaogang Yang ◽  
Shuyi Wang ◽  
Dongdong Shi ◽  
Chen Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Xenograft Model ◽  
Neutralizing Antibody ◽  
Tumor Stroma ◽  
Migration And Invasion ◽  
Tumor Associated Macrophages ◽  
Stat3 Pathway ◽  
M2 Polarization

Abstract Background: Tumor-associated macrophages (TAMs) in the tumor microenvironment influence tumor initiation, invasion and metastasis. Several studies have shown that Wnt5a is mainly expressed in the tumor stroma, especially in TAMs. However, whether Wnt5a regulates the polarization and biological function of TAMs in colorectal cancer (CRC) is incompletely understood. Methods: Immunofluorescence staining was performed to detect CD68 and Wnt5a expression in colorectal tissues from patients (63 CRC specimens VS 20 normal tissues). RT-qPCR, flow cytometry, ELISA and inhibitors were carried out to explore the role of Wnt5a in the polarization of TAMs. Clone formation and transwell assays were performed to determine the effects of Wnt5a–treated macrophages on tumor proliferation, migration and invasion in vitro. Finally, a xenograft model was applied to confirm the effects of Wnt5a + TAMs on CRC tumorigenesis. Results: We found that high Wnt5a + CD68 + /CD68 + TAMs ratio was significantly associated with poor prognosis in CRC patients and Wnt5a + TAM was an M2-like TAM subtype. Subsequently, we found that Wnt5a induced macrophages to secrete IL-10, which then acted as an autocrine cytokine to induce M2 polarization of these macrophages. IL-10 neutralizing antibody completely reversed the pro-M2 effect of Wnt5a. Mechanistically, the CaKMII-ERK1/2-STAT3 pathway was required for Wnt5a-mediated IL-10 expression in macrophages. Furthermore, Wnt5a-induced M2 macrophages promoted CRC cells proliferation, migration and invasion; knockdown of Wnt5a in TAMs significantly impaired the pro-tumor functions of TAMs. Conclusions: Our data indicate that Wnt5a could induce M2 polarization of TAMs by regulating CaKMII-ERK1/2-STAT3 pathway–mediated IL-10 secretion, ultimately promoting tumor growth and metastasis of CRC.

scholarly journals Circular RNA 100146 Promotes Colorectal Cancer Progression by miR-149/HMGA2 Axis

2020 ◽  
Author(s):  
Kunpeng Liu ◽  
Yuhua Mou ◽  
Xiufang Shi ◽  
Tingkun Liu ◽  
Zhanfeng Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Xenograft Model ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Western Blot Assay

Aim: Colorectal cancer (CRC) has developed into the third leading reason of cancer-associated death worldwide. Studies has confirmed that circular RNAs (circRNAs) sponge microRNAs (miRNAs) to regulate the function of downstream genes. This study aimed to expound the underlying mechanism of circRNA 100146 in CRC. Methods: The expression of circRNA 100146, miR-149 and high mobility group A2 (HMGA2) was detected by quantitative real time PCR (RT-qPCR). A series of bio-functional effects (cell viability, apoptosis, migration/invasion) were evaluated by methyl thiazolyl tetrazolium (MTT), flow cytometry, transwell. Protein level was measured by Western blot assay. The xenograft model was established for in vivo experiments. The interactions among circRNA 100146, miR-149 and HMGA2 were evaluated by dual-luciferase reporter assay, RNA immunoprecipitation assays, or RNA pulldown assay. Results: CircRNA 100146 was upregulated in CRC tissues and cells. CircRNA 100146 knockdown inhibited cell proliferation, promoted apoptosis and suppressed migration and invasion in vitro, and impeded tumor growth in vivo. Also, miR-149 was negalitively regulated by circRNA 100146, and targeted to HMGA2 and mediated its expression. Moreover, miR-149 interference abrogated the activities of silenced circRNA 100146 in proliferation, apoptosis, migration and invasion. Furthermore, HMGA2 overexpression abated the effects above caused by circRNA 100146 silencing, while the mutant on miR-149 binding sites in HMGA2 3’UTR lead to it losing this ability. Conclusion: CircRNA 100146 knockdown repressed proliferation, enhanced apoptosis and hindered migration and invasion in SW620 and SW480 cells through targeting miR-149/HMGA2 axis.

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.

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 NUSAP1 Promotes Gastric Cancer Progression Through Regulation of Yap Stability

2020 ◽  
Author(s):  
Hui Guo ◽  
Jianping Zou ◽  
Ling Zhou ◽  
Yan He ◽  
Miao Feng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Critical Role ◽  
Xenograft Model ◽  
Migration And Invasion

Abstract Background:Nucleolar and spindle associated protein (NUSAP1) is involved in tumor initiation, progression and metastasis. However, there are limited studies regarding the role of NUSAP1 in gastric cancer (GC). Methods: The expression profile and clinical significance of NUSAP1 in GC were analysed in online database using GEPIA, Oncomine and KM plotter, which was further confirmed in clinical specimens.The functional role of NUSAP1 were detected utilizing in vitro and in vivo assays. Western blotting, qRT-PCR, the cycloheximide-chase, immunofluorescence staining and Co-immunoprecipitaion (Co-IP) assays were performed to explore the possible molecular mechanism by which NUSAP1 stabilizes YAP protein. Results:In this study, we found that the expression of NUSAP1 was upregulated in GC tissues and correlates closely with progression and prognosis. Additionally, abnormal NUSAP1 expression promoted malignant behaviors of GC cells in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 physically interacts with YAP and furthermore stabilizes YAP protein expression, which induces the transcription of Hippo pathway downstream target genes. Furthermore, the effects of NUSAP1 on GC cell growth, migration and invasion were mainly mediated by YAP. Conclusions:Our data demonstrates that the novel NUSAP1-YAP axis exerts an critical role in GC tumorigenesis and progression, and therefore could provide a novel therapeutic target for GC treatment.

scholarly journals CSN8 is a key regulator in hypoxia-induced epithelial–mesenchymal transition and dormancy of colorectal cancer cells

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Songwen Ju ◽  
Feng Wang ◽  
Yirong Wang ◽  
Songguang Ju
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Treatment Conditions ◽  
Colorectal Cancer Cells

AbstractHypoxic stress plays a pivotal role in cancer progression; however, how hypoxia drives tumors to become more aggressive or metastatic and adaptive to adverse environmental stress is still poorly understood. In this study, we revealed that CSN8 might be a key regulatory switch controlling hypoxia-induced malignant tumor progression. We demonstrated that the expression of CSN8 increased significantly in colorectal cancerous tissues, which was correlated with lymph node metastasis and predicted poor patient survival. CSN8 overexpression induces the epithelial-mesenchymal transition (EMT) process in colorectal cancer cells, increasing migration and invasion. CSN8 overexpression arrested cell proliferation, upregulated key dormancy marker (NR2F1, DEC2, p27) and hypoxia response genes (HIF-1α, GLUT1), and dramatically enhanced survival under hypoxia, serum deprivation, or chemo-drug 5-fluorouracil treatment conditions. In particular, silenced CSN8 blocks the EMT and dormancy processes induced by the hypoxia of 1% O2 in vitro and undermines the adaptive capacity of colorectal cancer cells in vivo. The further study showed that CSN8 regulated EMT and dormancy partly by activating the HIF-1α signaling pathway, which increased HIF-1α mRNA expression by activating NF-κB and stabilized the HIF-1α protein via HIF-1α de-ubiquitination. Taken together, CSN8 endows primary colorectal cancer cells with highly aggressive/metastatic and adaptive capacities through regulating both EMT and dormancy induced by hypoxia. CSN8 could serve as a novel prognostic biomarker for colorectal cancer and would be an ideal target of disseminated dormant cell elimination and tumor metastasis, recurrence, and chemoresistance prevention.

scholarly journals miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 735 ◽  
Author(s):  
Kwang Seock Kim ◽  
Dongjun Jeong ◽  
Ita Novita Sari ◽  
Yoseph Toni Wijaya ◽  
Nayoung Jun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Xenograft Model ◽  
Mesenchymal Transition ◽  
Normal Tissues

Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b was significantly downregulated in both patient-derived CRC tissues and CRC cell lines compared to normal tissues and non-cancer cell lines. Also, miR551b significantly inhibited the motility of CRC cells in vitro, including migration, invasion, and wound healing rates, but did not affect cell proliferation. Mechanistically, miR551b targets and inhibits the expression of ZEB1 (Zinc finger E-box-binding homeobox 1), resulting in the dysregulation of EMT (epithelial-mesenchymal transition) signatures. More importantly, miR551b overexpression was found to reduce the tumor size in a xenograft model of CRC cells in vivo. Furthermore, bioinformatic analyses showed that miR551b expression levels were markedly downregulated in the advanced-stage CRC tissues compared to normal tissues, and ZEB1 was associated with the disease progression in CRC patients. Our findings indicated that miR551b could serve as a potential diagnostic biomarker and could be utilized to improve the therapeutic outcomes of CRC patients.

scholarly journals LncRNA DQ786243 contributes to proliferation and metastasis of colorectal cancer both in vitro and in vivo

2016 ◽  
Vol 36 (3) ◽  
Author(s):  
Longci Sun ◽  
Hanbing Xue ◽  
Chunhui Jiang ◽  
Hong Zhou ◽  
Lei Gu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Migration And Invasion ◽  
Cycle Progression ◽  
Proliferation And Metastasis ◽  
Non Coding Rnas ◽  
Colorectal Cancer Progression

This article aims to find the key long non-coding RNAs (LncRNAs) associated with colorectal cancer (CRC) and to study its biological functions in colorectal cancer progression. Our study has shown that upregulated LncRNA DQ786243 can regulate cell proliferation, cell cycle progression, cell apoptosis, migration, and invasion in CRC cells. Xenograft experiments confirmed that the growth of xenograft tumors formed by CRC cells was suppressed after silencing LncRNA DQ786243 expression. In conclusion, our study suggests that LncRNA DQ786243 is an oncogene that promotes tumor progression and leads us to propose that LncRNAs may serve as key regulatory hubs in CRC progression.

scholarly journals Cancer-Associated Fibroblasts in Pancreatic Cancer: Should They Be Deleted or Reeducated?

2018 ◽  
Vol 17 (4) ◽  
pp. 1016-1019 ◽  
Author(s):  
Chao Qu ◽  
Qing Wang ◽  
Zhiqiang Meng ◽  
Peng Wang
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Cancer Associated Fibroblasts

Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.

scholarly journals The Long Noncoding RNA HOTAIR Promotes Colorectal Cancer Progression by Sponging miR-197

2018 ◽  
Vol 26 (3) ◽  
pp. 473-481 ◽  
Author(s):  
Xinyang Lu ◽  
Zhiqiang Liu ◽  
Xiaofei Ning ◽  
Lunhua Huang ◽  
Biao Jiang
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Migration And Invasion ◽  
Downstream Target ◽  
Potential Applications ◽  
Colorectal Cancer Progression

The long noncoding RNA HOX transcript antisense RNA (HOTAIR) has been found to be overexpressed in many human malignancies and involved in tumor progression and metastasis. Although the downstream target through which HOTAIR modulates tumor metastasis is not well known, evidence suggests that microRNA-197 (miR-197) might be involved in this event. In the present study, the significance of HOTAIR and miR-197 in the progression of colorectal cancer was detected in vitro and in vivo. We found that HOTAIR expression was significantly increased in colorectal cancer cells and tissues. In contrast, the expression of miR-197 was obviously decreased. We further demonstrated that HOTAIR knockdown promoted apoptosis and inhibited cell proliferation, migration, and invasion in vitro and in vivo. Moreover, HOTAIR modulated the progression of colorectal cancer by competitively binding miR-197. Taken together, our study has identified a novel pathway through which HOTAIR exerts its oncogenic role and provided a molecular basis for potential applications of HOTAIR in the prognosis and treatment of colorectal cancer.

Sign in / Sign up

Export Citation Format

Share Document