scholarly journals Pals1 prevents Rac1-dependent colorectal cancer cell metastasis by inhibiting Arf6

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Simona Mareike Lüttgenau ◽  
Christin Emming ◽  
Thomas Wagner ◽  
Julia Harms ◽  
Justine Guske ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Scaffolding Protein ◽  
Migration And Invasion ◽  
Tight Junction Formation ◽  
Cell Metastasis ◽  
Colorectal Cancer Cells

AbstractLoss of apical-basal polarity and downregulation of cell-cell contacts is a critical step during the pathogenesis of cancer. Both processes are regulated by the scaffolding protein Pals1, however, it is unclear whether the expression of Pals1 is affected in cancer cells and whether Pals1 is implicated in the pathogenesis of the disease.Using mRNA expression data and immunostainings of cancer specimen, we show that Pals1 is frequently downregulated in colorectal cancer, correlating with poorer survival of patients. We further found that Pals1 prevents cancer cell metastasis by controlling Rac1-dependent cell migration through inhibition of Arf6, which is independent of the canonical binding partners of Pals1. Loss of Pals1 in colorectal cancer cells results in increased Arf6 and Rac1 activity, enhanced cell migration and invasion in vitro and increased metastasis of transplanted tumor cells in mice. Thus, our data reveal a new function of Pals1 as a key inhibitor of cell migration and metastasis of colorectal cancer cells. Notably, this new function is independent of the known role of Pals1 in tight junction formation and apical-basal polarity.

scholarly journals 2, 3-Dihydro-3β-methoxy Withaferin-A Lacks Anti-Metastasis Potency: Bioinformatics and Experimental Evidences

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Anupama Chaudhary ◽  
Rajkumar S. Kalra ◽  
Vidhi Malik ◽  
Shashank P. Katiyar ◽  
Durai Sundar ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Human Cancer ◽  
Effector Proteins ◽  
Withaferin A ◽  
Migration And Invasion ◽  
Cell Metastasis

AbstractWithaferin-A is a withanolide, predominantly present in Ashwagandha (Withania somnifera). It has been shown to possess anticancer activity in a variety of human cancer cells in vitro and in vivo. Molecular mechanism of such cytotoxicity has not yet been completely understood. Withaferin-A and Withanone were earlier shown to activate p53 tumor suppressor and oxidative stress pathways in cancer cells. 2,3-dihydro-3β-methoxy analogue of Withaferin-A (3βmWi-A) was shown to lack cytotoxicity and well tolerated at higher concentrations. It, on the other hand, protected normal cells against oxidative, chemical and UV stresses through induction of anti-stress and pro-survival signaling. We, in the present study, investigated the effect of Wi-A and 3βmWi-A on cell migration and metastasis signaling. Whereas Wi-A binds to vimentin and heterogeneous nuclear ribonucleoprotein K (hnRNP-K) with high efficacy and downregulates its effector proteins, MMPs and VEGF, involved in cancer cell metastasis, 3βmWi-A was ineffective. Consistently, Wi-A, and not 3βmWi-A, caused reduction in cytoskeleton proteins (Vimentin, N-Cadherin) and active protease (u-PA) that are essential for three key steps of cancer cell metastasis (EMT, increase in cell migration and invasion).

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 Xanthium strumarium Fruit Extract Inhibits ATG4B and Diminishes the Proliferation and Metastatic Characteristics of Colorectal Cancer Cells

Toxins ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 313 ◽  
Author(s):  
Hsueh-Wei Chang ◽  
Pei-Feng Liu ◽  
Wei-Lun Tsai ◽  
Wan-Hsiang Hu ◽  
Yu-Chang Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Plant Extracts ◽  
Migration And Invasion ◽  
Xanthium Strumarium ◽  
Autophagic Flux ◽  
Tribulus Terrestris ◽  
Fruit Extract ◽  
Colorectal Cancer Cells

Autophagy is an evolutionarily conserved pathway to degrade damaged proteins and organelles for subsequent recycling in cells during times of nutrient deprivation. This process plays an important role in tumor development and progression, allowing cancer cells to survive in nutrient-poor environments. The plant kingdom provides a powerful source for new drug development to treat cancer. Several plant extracts induce autophagy in cancer cells. However, little is known about the role of plant extracts in autophagy inhibition, particularly autophagy-related (ATG) proteins. In this study, we employed S-tagged gamma-aminobutyric acid receptor associated protein like 2 (GABARAPL2) as a reporter to screen 48 plant extracts for their effects on the activity of autophagy protease ATG4B. Xanthium strumarium and Tribulus terrestris fruit extracts were validated as potential ATG4B inhibitors by another reporter substrate MAP1LC3B-PLA2. The inhibitory effects of the extracts on cellular ATG4B and autophagic flux were further confirmed. Moreover, the plant extracts significantly reduced colorectal cancer cell viability and sensitized cancer cells to starvation conditions. The fruit extract of X. strumarium consistently diminished cancer cell migration and invasion. Taken together, the results showed that the fruit of X. strumarium may have an active ingredient to inhibit ATG4B and suppress the proliferation and metastatic characteristics of colorectal cancer cells.

Effect of JAG2 on migration and invasion in colorectal cancer cell by PRAF2, independent of epithelial-mesenchymal transition.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15107-e15107
Author(s):  
Wan He ◽  
Han Wu ◽  
Dongcheng Liu ◽  
Wenwen Li ◽  
Ruilian Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Lines ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Cells ◽  
Cancer Tissues

e15107 Background: Our previous studies revealed the increased expression of Jagged 2 (JAG2) in most intestinal cancer tissues. In colon cancer cell lines, JAG2 involved in the regulation of migration and invasion without affecting cell proliferation. This study further explored the mechanisms of how JAG2 promotes migration and invasion of colorectal cancer cells. Methods: We analyzed the expression of JAG2 mRNA and protein in normal human colon tissue cells and colorectal cancer cells. The promotive role of JAG2 in migration and invasion was tested by JAG2 siRNA and JAG2 overexpression in various colon cancer cell lines. To understand the mechanisms, we first treated HT29 cells with LY2157299, a TGF-β signaling pathway inhibitor, and Slug siRNA, to identify the cross-talk between JAG2 and EMT pathway. In addition, co-expression status of JAG2 and TGF-β-induced epithelial-mesenchymal transition (EMT) markers was analyzed. Finally, by using siRNA and proteomics technology, co-expressed proteins of JAG2 in colorectal cancer cells were identified. Results: JAG2 was abnormally expressed in colorectal cancer tissues and directly related with clinical stages. Similar to the findings in human tissues, the expression of both JAG2 mRNA and protein was significantly increased in the colorectal cancer cell lines compared with that of normal colorectal cell line CCD18-Co. Interestingly, the promotion of JAG2 in migration and invasion was independent of EMT pathway. Furthermore, we found that the expression of JAG2 was correlated with PRAF2 (PRA1 Domain Family Member 2), a protein involved in the formation of exosome-like vesicles. In the presence of PRAF2, JAG2-rich exosome promoted migration and invasion. JAG2 might regulate the migration and invasion of colon cell through PRAF2. Conclusions: This is the evidence supporting the biological function of JAG2 in migration and invasion through non-EMT-dependent pathways and also the first exploration of the role of PRAF2 in colorectal cancer cells. These findings provide the theoretical basis for potential targeted therapy against JAG2/PRAF2.

scholarly journals LPS Upregulated VEGFR-3 Expression Promote Migration and Invasion in Colorectal Cancer via a Mechanism of Increased NF-κB Binding to the Promoter of VEGFR-3

2016 ◽  
Vol 39 (5) ◽  
pp. 1665-1678 ◽  
Author(s):  
Guangwei Zhu ◽  
Qiang Huang ◽  
Wei Zheng ◽  
Yongjian Huang ◽  
Jin Hua ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Neutralizing Antibody ◽  
High Expression ◽  
Migration And Invasion ◽  
Colorectal Cancer Cells ◽  
Cancer Tissues ◽  
The Relationship

Background and Aim: Lipopolysaccharide(LPS) could promote the progression of colorectal cancer, but the specific regulatory mechanisms are largely unknown. So, this study aim to clarify the mechanisms that LPS upregulated VEGFR-3, which promotes colorectal cancer cells migration and invasion with a mechanism of increased NF-κB bind to the promoter of VEGFR-3. Methods: The present study examined the VEGFR-3 expression in colorectal cancer tissues and analyzed the relationship between the VEGFR-3 expression with clinical parameters. PCR, Western blot, CCK-8, colone formation assay, and Transwell assay detected that LPS promoted the migration and invasion and the role of VEGFR-3 in the process of colorectal carcinoma in vitro. Used the methods of promoter analysis, EMSA assay and ChIP assay to explore the mechanisms LPS increased the expression of VEGFR-3. Results: VEGFR-3 was significantly high expression in the colorectal cancer tissues. And the high expression was associated with the TNM stage and lymph node metastasis of colorectal cancer. LPS could promote the migration and invasion, which could be blocked by the neutralizing antibody IgG of VEGFR-3. And found that -159 nt to +65 nt was the crucial region of VEGFR-3 promoter. And detected that the NF-κB was important transcription factor for the VEGFR-3 promoter. And LPS could increase NF-κB binding to VEGFR-3 promoter and upregulated the expression of VEGFR-3 to exert biological functions. Conclusion: We have elucidated the relationship between LPS and the VEGFR-3 expression and revealed that VEGFR-3 play very important role in the process of LPS promoting the migration and invasion of colorectal cancer cells. Further illuminated the mechanism that LPS upregulated VEGFR-3 expression via increased NF-κB bind to the promoter of VEGFR-3.

scholarly journals Correlation between FAK and EGF-Induced EMT in Colorectal Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Kun Huang ◽  
Ningning Gao ◽  
Donglin Bian ◽  
Qixi Zhai ◽  
Puxu Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Egfr Signaling Pathway ◽  
Colorectal Cancer Cells ◽  
E Cadherin

Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and metastasis of colorectal cancer, which is mediated by FAK and EGF. However, whether FAK participates in EMT in colorectal cancer cells through the EGF/EGFR signaling pathway remains unknown. The aim of this study was to investigate the effector mechanisms of FAK in the process of EGF-induced EMT in colorectal cancer cells and to determine whether miR-217 is involved in this process. Caco-2 cancer cells were routinely cultured with and without treatment with 100 ng/mL EGF, and changes in cell morphology were observed using an inverted microscope. In addition, a transwell assay was used to detect cell migration under the condition of EGF treatment. The expression of FAK, pFAK, E-cadherin, vimentin, and β actin was assessed by western blotting, and the expression of miR-217 was assessed using real-time PCR. We found that EGF induced EMT in colorectal cancer cells and enhanced cell migration and invasion ability. Moreover, FAK was involved in the EGF-induced EMT of colorectal cancer cells. EGF upregulated the expression of E-cadherin in colorectal cancer cells by activating FAK, and miR-217 was found to participate in EGF-induced EMT in colorectal cancer cells. Our findings indicate that EGF induces EMT in colorectal cancer cells by activating FAK, and miR-217 is involved in the EGF/FAK/E-cadherin signaling pathway.

scholarly journals Anillin regulates breast cancer cell migration, growth, and metastasis by non-canonical mechanisms involving control of cell stemness and differentiation

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Dongdong Wang ◽  
Nayden G. Naydenov ◽  
Mikhail G. Dozmorov ◽  
Jennifer E. Koblinski ◽  
Andrei I. Ivanov
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Migration And Invasion ◽  
Tumor Growth And Metastasis

Abstract Background Breast cancer metastasis is driven by a profound remodeling of the cytoskeleton that enables efficient cell migration and invasion. Anillin is a unique scaffolding protein regulating major cytoskeletal structures, such as actin filaments, microtubules, and septin polymers. It is markedly overexpressed in breast cancer, and high anillin expression is associated with poor prognosis. The aim of this study was to investigate the role of anillin in breast cancer cell migration, growth, and metastasis. Methods CRISPR/Cas9 technology was used to deplete anillin in highly metastatic MDA-MB-231 and BT549 cells and to overexpress it in poorly invasive MCF10AneoT cells. The effects of anillin depletion and overexpression on breast cancer cell motility in vitro were examined by wound healing and Matrigel invasion assays. Assembly of the actin cytoskeleton and matrix adhesion were evaluated by immunofluorescence labeling and confocal microscopy. In vitro tumor development was monitored by soft agar growth assays, whereas cancer stem cells were examined using a mammosphere formation assay and flow cytometry. The effects of anillin knockout on tumor growth and metastasis in vivo were determined by injecting control and anillin-depleted breast cancer cells into NSG mice. Results Loss-of-function and gain-of-function studies demonstrated that anillin is necessary and sufficient to accelerate migration, invasion, and anchorage-independent growth of breast cancer cells in vitro. Furthermore, loss of anillin markedly attenuated primary tumor growth and metastasis of breast cancer in vivo. In breast cancer cells, anillin was localized in the nucleus; however, knockout of this protein affected the cytoplasmic/cortical events, e.g., the organization of actin cytoskeleton and cell-matrix adhesions. Furthermore, we observed a global transcriptional reprogramming of anillin-depleted breast cancer cells that resulted in suppression of their stemness and induction of the mesenchymal to epithelial trans-differentiation. Such trans-differentiation was manifested by the upregulation of basal keratins along with the increased expression of E-cadherin and P-cadherin. Knockdown of E-cadherin restored the impaired migration and invasion of anillin-deficient breast cancer cells. Conclusion Our study demonstrates that anillin plays essential roles in promoting breast cancer growth and metastatic dissemination in vitro and in vivo and unravels novel functions of anillin in regulating breast cancer stemness and differentiation.

scholarly journals RANK promotes colorectal cancer migration and invasion by activating the Ca2+-calcineurin/NFATC1-ACP5 axis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Qian Liang ◽  
Yun Wang ◽  
Yingsi Lu ◽  
Qingqing Zhu ◽  
Wenlin Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Nuclear Translocation ◽  
Migration And Invasion ◽  
Tartrate Resistant Acid Phosphatase ◽  
Activated T Cells ◽  
Cell Migration And Invasion ◽  
Cell Metastasis

AbstractThe tumor necrosis factor (TNF) receptor superfamily member 11a (TNFRSF11a, also known as RANK) was demonstrated to play an important role in tumor metastasis. However, the specific function of RANK in colorectal cancer (CRC) metastasis and the underlying mechanism are unknown. In this study, we found that RANK expression was markedly upregulated in CRC tissues compared with that in matched noncancerous tissues. Increased RANK expression correlated positively with metastasis, higher TNM stage, and worse prognosis in patients with CRC. Overexpression of RANK promoted CRC cell metastasis in vitro and in vivo, while knockdown of RANK decreased cell migration and invasion. Mechanistically, RANK overexpression significantly upregulated the expression of tartrate-resistant acid phosphatase 5 (TRAP/ACP5) in CRC cells. Silencing of ACP5 in RANK-overexpressing CRC cells attenuated RANK-induced migration and invasion, whereas overexpression of ACP5 increased the migration and invasion of RANK-silencing cells. The ACP5 expression was transcriptionally regulated by calcineurin/nuclear factor of activated T cells c1 (NFATC1) axis. The inhibition of calcineurin/NFATC1 significantly decreased ACP5 expression, and attenuated RANK-induced cell migration and invasion. Furthermore, RANK induced phospholipase C-gamma (PLCγ)-mediated inositol-1,4,5-trisphosphate receptor (IP3R) axis and stromal interaction molecule 1 (STIM1) to evoke calcium (Ca2+) oscillation. The RANK-mediated intracellular Ca2+ mobilization stimulated calcineurin to dephosphorylate NFATC1 and induce NFATC1 nuclear translocation. Both blockage of PLCγ-IP3R axis and STIM1 rescued RANK-induced NFATC1 nuclear translocation, ACP5 expression, and cell metastasis. Our study revealed the functional expression of RANK in human CRC cells and demonstrated that RANK induced the Ca2+-calcineurin/NFATC1-ACP5 axis in the regulation of CRC metastasis, that might be amenable to therapeutic targeting.

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