scholarly journals TBX3 acts as tissue-specific component of the Wnt/β-catenin enhanceosome

2020 ◽  
Author(s):  
Dario Zimmerli ◽  
Costanza Borrelli ◽  
Amaia Jauregi-Miguel ◽  
Simon Söderholm ◽  
Salome Brütsch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Target Genes ◽  
Metastatic Potential ◽  
Regulatory Elements ◽  
Dependent Manner ◽  
Independent Manner ◽  
Tissue Specific ◽  
Colorectal Cancer Cells

AbstractBCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signalling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, TBX3 and BCL9 co-occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as a new, context-dependent component of the Wnt/β-catenin-dependent enhanceosome.

scholarly journals TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Dario Zimmerli ◽  
Costanza Borrelli ◽  
Amaia Jauregi-Miguel ◽  
Simon Söderholm ◽  
Salome Brütsch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Target Genes ◽  
Regulatory Elements ◽  
Dependent Manner ◽  
Independent Manner ◽  
Tissue Specific ◽  
Colorectal Cancer Cells ◽  
Transcriptional Complex

BCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/β-catenin-dependent transcriptional complex.

scholarly journals PLAC1 Enhances Metastatic Potential and is Associated with PI3K/AKT/NF-κB Signaling Pathway in Colon Cancer

2019 ◽  
Author(s):  
JIachi Ma ◽  
Shoukai Zhang ◽  
Danru Liang ◽  
Lei Li ◽  
Jun Du ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Umbilical Vein ◽  
Metastatic Potential ◽  
Dependent Manner ◽  
Human Colorectal Cancer ◽  
Colorectal Cancer Cells ◽  
Metastatic Process ◽  
Ht 29

Abstract Background: To better explore the underlying mechanism of liver metastatic formation by placenta-specific protein 1 (PLAC1) in human colorectal cancer, we investigated the proliferation, invasion and angiogenic capabilities of human colorectal cancer cell lines with different liver metastatic potentials as well as the mechanism of action of PLAC1 in the metastatic process. Methods: The expression of PLAC1 was detected by reverse transcriptase PCR, western blot and real-time PCR. The effect of PLAC1 on metastatic potential was determined by proliferation, invasion, and angiogenesis assays, including an in vitro coculture system consisting of cancer cells and vascular endothelial cells that were used to detect the relationship between cancer cells and angiogenesis. In addition, we also determined PLAC1 downstream targets that preferentially contribute to the metastatic process. Results: PLAC1 was expressed in HT-29, WiDr and CaCo-2 colorectal cancer cells but not in Colo320 colorectal cancer cells. PLAC1 could not only significantly enhance the proliferation of CoLo320 and human umbilical vein endothelial cells (HUVECs) but could also promote the invasion of CoLo320 cells. The angiogenesis of HUVECs was enhanced by PLAC1 in a dose-dependent manner. In cocultured systems, angiogenesis was significantly increased by coculture with HT-29 cells. In addition, PLAC1 could promote angiogenesis in coculture with HT-29 cells. Furthermore, PLAC1-enhanced metastatic potential of colorectal cancer cells was dependent on activation of the PI3K/Akt/NF-κB pathway. Conclusions: The activation of PI3K/Akt/NF-κB signaling by PLAC1 may be critical for the metastasis of colorectal cancer cells. According to our results, we suggest that modification of PLAC1 function might be a promising new therapeutic approach to inhibit the aggressive spread of colorectal cancer.

scholarly journals Placenta-Specific Protein 1 Enhances Liver Metastatic Potential and is Associated with the PI3K/AKT/NF-κB Signaling Pathway in Colorectal Cancer

2020 ◽  
Author(s):  
Jiachi Ma ◽  
Lei Li ◽  
Jun Du ◽  
Chengwu Pan ◽  
Chensong Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Metastatic Potential ◽  
Specific Protein ◽  
Dependent Manner ◽  
Human Colorectal Cancer ◽  
Colorectal Cancer Cells ◽  
Metastatic Process ◽  
Ht 29

Abstract Abstract Background: To better explore the underlying mechanism of liver metastatic formation by placenta-specific protein 1 (PLAC1) in human colorectal cancer, we investigated the proliferation, invasion and angiogenic capabilities of human colorectal cancer cell lines with different liver metastatic potentials as well as the mechanism of action of PLAC1 in the metastatic process. Methods: The expression of PLAC1 was detected by reverse transcriptase PCR, western blot and real-time PCR. The effect of PLAC1 on metastatic potential was determined by proliferation, invasion, and angiogenesis assays, including an in vitro coculture system consisting of cancer cells and vascular endothelial cells that were used to detect the relationship between cancer cells and angiogenesis. In addition, we also determined PLAC1 downstream targets that preferentially contribute to the metastatic process. Results: PLAC1 was expressed in HT-29, WiDr and CaCo-2 colorectal cancer cells but not in Colo320 colorectal cancer cells. PLAC1 not only enhanced significantly the proliferation of CoLo320 and human umbilical vein endothelial cells (HUVECs), but also promoted the invasion of CoLo320 cells. The angiogenesis of HUVECs was enhanced by PLAC1 in a dose-dependent manner. In cocultured systems, angiogenesis was significantly increased by coculture with HT-29 cells. In addition, PLAC1 could promote angiogenesis in coculture with HT-29 cells. Furthermore, PLAC1-enhanced metastatic potential of colorectal cancer cells was dependent on activation of the PI3K/Akt/NF-κB pathway. Conclusions: The activation of PI3K/Akt/NF-κB signaling by PLAC1 may be critical for the metastasis of colorectal cancer cells. According to our results, we suggest that modification of PLAC1 function might be a promising new therapeutic approach to inhibit the aggressive spread of colorectal cancer.

scholarly journals PGE2-JNK signaling axis non-canonically promotes Gli activation by protecting Gli2 from ubiquitin-proteasomal degradation

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jun Yang ◽  
Juan Wang ◽  
Yuan Liu ◽  
Yu Zhang ◽  
Wenjing Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Proteasomal Degradation ◽  
Colorectal Cancers ◽  
Independent Manner ◽  
Colorectal Cancer Cells ◽  
Signaling Axis ◽  
Colorectal Cancer Patients

AbstractBoth bench and bedside investigations have challenged the supportive role of Hedgehog (Hh) activity in the progression of colorectal cancers, thus raising a critical need to further deeply determine the contribution of Hh to the growth of colorectal cancer. Combining multiple complementary means, including in vitro and in vivo inflammatory colorectal cancer models, and pathological analysis of clinical colorectal cancer patients samples. We report that colorectal cancer cells hijack prostaglandin E2 (PGE2) to non-canonically promote Hh transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner. Mechanistically, PGE2 activates c-Jun N-terminal kinase (JNK), which in turn enables Gli2 to evade ubiquitin-proteasomal degradation by phosphorylating Gli2 at Thr1546. This study not only presents evidence for understanding the contribution of Hh to colorectal cancers, but also provides a novel molecular portrait underlying how PGE2-activated JNK fine-tunes the evasion of Gli2 from ubiquitin-proteasomal degradation. Therefore, it proposes a rationale for the future evaluation of chemopreventive and selective therapeutic strategies for colorectal cancers by targeting PGE2-JNK-Gli signaling route.

scholarly journals Placenta-Specific Protein 1 Enhances Metastatic Potential and is Associated with the PI3K/AKT/NF-κB Signaling Pathway in Colorectal Cancer

2020 ◽  
Author(s):  
Jiachi Ma ◽  
Lei Li ◽  
Jun Du ◽  
Chengwu Pan ◽  
Chensong Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Metastatic Potential ◽  
Specific Protein ◽  
Dependent Manner ◽  
Human Colorectal Cancer ◽  
Colorectal Cancer Cells ◽  
Metastatic Process ◽  
Ht 29

Abstract Background To better explore the underlying mechanism of liver metastatic formation by placenta-specific protein 1 (PLAC1) in human colorectal cancer, we investigated the proliferation, invasion and angiogenic capabilities of human colorectal cancer cell lines with different liver metastatic potentials as well as the mechanism of action of PLAC1 in the metastatic process. Methods The expression of PLAC1 was detected by reverse transcriptase PCR, western blot and real-time PCR. The effect of PLAC1 on metastatic potential was determined by proliferation, invasion, and angiogenesis assays, including an in vitro coculture system consisting of cancer cells and vascular endothelial cells that were used to detect the relationship between cancer cells and angiogenesis. In addition, we also determined PLAC1 downstream targets that preferentially contribute to the metastatic process. Results PLAC1 was expressed in HT-29, WiDr and CaCo-2 colorectal cancer cells but not in Colo320 colorectal cancer cells. PLAC1 could not only significantly enhance the proliferation of CoLo320 and human umbilical vein endothelial cells (HUVECs) but could also promote the invasion of CoLo320 cells. The angiogenesis of HUVECs was enhanced by PLAC1 in a dose-dependent manner. In cocultured systems, angiogenesis was significantly increased by coculture with HT-29 cells. In addition, PLAC1 could promote angiogenesis in coculture with HT-29 cells. Furthermore, PLAC1-enhanced metastatic potential of colorectal cancer cells was dependent on activation of the PI3K/Akt/NF-κB pathway. Conclusions The activation of PI3K/Akt/NF-κB signaling by PLAC1 may be critical for the metastasis of colorectal cancer cells. According to our results, we suggest that modification of PLAC1 function might be a promising new therapeutic approach to inhibit the aggressive spread of colorectal cancer.

scholarly journals Scaphium affine Ethanol Extract Induces Anoikis by Regulating the EGFR/Akt Pathway in HCT116 Colorectal Cancer Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Hye Won Kawk ◽  
Gun-He Nam ◽  
Myeong Jin Kim ◽  
Sang-Yong Kim ◽  
Young-Min Kim
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Hct116 Cell ◽  
Akt Pathway ◽  
Dependent Manner ◽  
Anticancer Effects ◽  
Colorectal Cancer Cells ◽  
Dose Dependent

Scaphium affine ethanol extracts (SAE) is a species that has been shown to contain various physiological effects; however, its anticancer effects have yet to be revealed. We qualitatively evaluated β-sitosterol in SAE through high-performance liquid chromatography (HPLC). The cytotoxicity in HCT116 and HT29 colorectal cancer cells and CCD841 normal colon cells was confirmed through WST-1 assays. Selective cytotoxicity was observed in colorectal cancer cells, with greater cytotoxicity demonstrated in the HCT116 cell line. As such, the HCT116 colorectal cell line was selected for subsequent experiments. After HCT116 cells were treated with SAE, it was confirmed that the apoptosis rate was increased in a SAE dose-dependent manner through Annexin V assay. SAE further showed dose-dependent suppression of invasion through invasion assays. Anoikis induction through the EGFR/Akt pathway in HCT116 colorectal cancer cells was confirmed by Western blotting. The tumor suppressive effects of SAE was assessed in vivo using a xenograft model of human HCT116 colorectal cancer cells. As a result, we confirmed that SAE decreased tumor size in a dose-dependent manner and that p-EGFR and cleaved-caspase 3 in tumors were also regulated in a dose-dependent manner. This study showed that SAE, by containing β-sitosterol with proven anticancer effects, induces anoikis through the EGFR/Akt pathway in HCT116 colorectal cancer cells both in vitro and in vivo.

scholarly journals Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility

BMC Cancer ◽  
2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Hui-min Zhou ◽  
Yuan-yuan Fang ◽  
Paul M. Weinberger ◽  
Ling-ling Ding ◽  
John K. Cowell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Motility ◽  
Cancer Cells ◽  
Metastatic Potential ◽  
Expression Of Genes ◽  
Colorectal Cancer Cells

scholarly journals Decyl caffeic acid inhibits the proliferation of colorectal cancer cells in an autophagy-dependent manner in vitro and in vivo

PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0232832 ◽  
Author(s):  
Ching Chen ◽  
Yueh-Hsiung Kuo ◽  
Cheng-Chieh Lin ◽  
Che-Yi Chao ◽  
Man-Hui Pai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Caffeic Acid ◽  
Dependent Manner ◽  
Colorectal Cancer Cells

scholarly journals Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Changhong Li ◽  
Kui Zhang ◽  
Guangzhao Pan ◽  
Haoyan Ji ◽  
Chongyang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Growth ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Xenograft ◽  
Anticancer Activities ◽  
Colorectal Cancer Cells

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

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