RNA interference of osteopontin inhibits in vitro and in vivo colon cancer metastasis

2004 ◽  
Vol 121 (2) ◽  
pp. 300
Author(s):  
P.Y. Wai ◽  
Z. Mi ◽  
H. Guo ◽  
S. Sarraf-Yazdi ◽  
B. Clary ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Rna Interference ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis

scholarly journals Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Shiue-Wei Lai ◽  
Ming-Yao Chen ◽  
Oluwaseun Adebayo Bamodu ◽  
Ming-Shou Hsieh ◽  
Ting-Yi Huang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Growth Factor ◽  
Cell Lines ◽  
Distant Metastasis ◽  
Cancer Metastasis ◽  
Lovo Cell ◽  
Promoting Effect ◽  
Colon Cancer Metastasis

Background. Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. Methods. Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). Results. The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. Conclusion. Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.

Role of endothelin a receptor in colon cancer metastasis: In vitro and in vivo evidence

2013 ◽  
Vol 53 (S1) ◽  
pp. E85-E91 ◽  
Author(s):  
Shaolin Nie ◽  
Jumei Zhou ◽  
Fei Bai ◽  
Bonian Jiang ◽  
Juying Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis ◽  
Endothelin A Receptor ◽  
Endothelin A

scholarly journals Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazim Husain ◽  
Domenico Coppola ◽  
Chung S. Yang ◽  
Mokenge P. Malafa
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Metastasis ◽  
Annexin V ◽  
Cancer Cell Growth ◽  
Ki 67 ◽  
Sox2 Expression ◽  
Tumour Metastasis

AbstractThe activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/β-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and β-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

scholarly journals Hypoxia-Induced LIN28A mRNA Promotes the Metastasis of Colon Cancer in a Protein-Coding-Independent Manner

2021 ◽  
Vol 9 ◽  
Author(s):  
Mingjiao Weng ◽  
Yukuan Feng ◽  
Yan He ◽  
Weiwei Yang ◽  
Jing Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Mrna Level ◽  
Unexpected Finding ◽  
Independent Manner ◽  
Protein Coding ◽  
P Bodies

The hypoxic microenvironment is beneficial to the metastasis but not to the proliferation of cancer cells. However, the mechanisms regarding to hypoxia differentially regulating cancer metastasis and proliferation are largely unknown. In this study, we revealed that hypoxia induced the expression of LIN28A at mRNA level but segregated LIN28A mRNAs in the P-bodies and thus inhibits the production of LIN28A protein. This unexpected finding suggests that there may be non-coding role for LIN28A mRNA in the progression of colon cancer. We further showed that the non-coding LIN28A mRNA promotes the metastasis but not proliferation of colon cancer cells in vitro and in vivo. Mechanistically, we revealed that methionyl aminopeptidase 2 (METAP2) is one of the up-regulated metastasis regulators upon over-expression of non-coding LIN28A identified by mass spectrum, and confirmed that it is non-coding LIN28A mRNA instead of LIN28A protein promotes the expression of METAP2. Moreover, we demonstrated that knockdown of DICER abolished the promotional effects of non-coding LIN28A on the metastasis and METAP2 expression. Conclusively, we showed that hypoxia induces the production of LIN28A mRNAs but segregated them into the P-bodies together with miRNAs targeting both LIN28A and METAP2, and then promotes the metastasis by positively regulating the expression of METAP2. This study uncovered a distinctive role of hypoxia in manipulating the metastasis and proliferation by differently regulating the expression of LIN28A at mRNA and protein level.

Inactivation of E-cadherin by Trop-2 drives colon cancer metastasis.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 105-105
Author(s):  
Saverio Alberti ◽  
Emanuela Guerra ◽  
Donato F. Altomare ◽  
Raffaella Depalo ◽  
Marco Trerotola
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis ◽  
Metastatic Relapse ◽  
Metastatic Spreading ◽  
E Cadherin ◽  
Cell Cell

105 Background: Tumor metastasis is the main cause of death of colon cancer patients and the biggest hurdle for cancer cure. We set to identify decisive drivers and of pivotal therapy targets for colon cancer metastasis. Methods: IHC analysis quantified the expression of target molecules in primary tumors and metastases. Cell-cell adhesion capacity was assessed in vitro and in HCT116 colon cancer cell spheroids. Pre-clinical models of orthotopic growth of KM12SM colon cancer cells and metastatic diffusion to the liver were utilized to assess metastatic spreading force of wtTrop-2 and of the constitutively-active, tail-less form of Trop-2 (Δcyto). Xenotransplant and metastasis transcriptomes were analyzed for differential induction of EMT determinants. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in independent case series of colon cancer patients. Results: wtTrop-2 was shown to induce wound-healing. ΔcytoTrop-2 further increased cell migration ability. Both wtTrop-2 and ΔcytoTrop-2 induced resistance to apoptosis in vitro and in vivo. wtTrop-2 strikingly increased the metastatic capacity of KM12SM cells, raising metastasis rates from 45% for control cells to 90% for wtTrop-2 transfectants. The constitutively-active ΔcytoTrop-2 further boosted metastatic spreading, with metastatic livers reaching up to four times their normal size. Cancer metastases revealed high levels of E-cadherin, in the absence of transcriptional down-regulation. EMT transcription factors were largely missing from Trop-2-activated cells. Rather, binding to Trop-2 was shown to cause the release of E-cadherin from the cytoskeleton, loss of cell-cell adhesion and activation of β-catenin. This global, Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in colon cancer patients and was shown to impact on colon cancer metastatic relapse and overall patient survival. Conclusions: We identify Trop-2-driven functional inactivation of E-cadherin as a widespread driver of metastatic diffusion in colon cancer, opening novel avenues for personalized diagnostic procedures and anti-cancer therapies. [Table: see text]

scholarly journals RSK2 phosphorylates T-bet to attenuate colon cancer metastasis and growth

2017 ◽  
Vol 114 (48) ◽  
pp. 12791-12796 ◽  
Author(s):  
Ke Yao ◽  
Cong Peng ◽  
Yuwen Zhang ◽  
Tatyana A. Zykova ◽  
Mee-Hyun Lee ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Liver Metastasis ◽  
Cancer Metastasis ◽  
Mononuclear Cells ◽  
Kinase Assay ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Colon Cancer Metastasis ◽  
Ribosomal S6 Kinase

Metastasis is a major cause of cancer-related deaths. Approximately 80% of patients with colorectal cancer develop liver metastasis and 20% develop lung metastasis. We found that at different stages of colon cancer, IFNγ secretion from peripheral blood mononuclear cells was decreased compared with healthy controls. The ribosomal S6 kinase (RSK) family of kinases has multiple cellular functions, and we examined their roles in this observed IFNγ decrease. Flow cytometry analysis of wild-type (WT) and RSK2 knockout (KO) mice revealed significantly lower levels of IFNγ in the RSK2 KO mice compared with the WT mice. Since IFNγ is a component of immunity, which contributes to protection against metastatic carcinomas, we conducted a colon cancer liver metastasis experiment. We found significantly greater metastasis in RSK2 KO mice compared with WT mice. Transcription factor T-bet can directly activate Ifnγ gene transcription. In vitro kinase assay results showed that RSK2 phosphorylated T-bet at serines 498 and 502. We show that phosphorylation of T-bet by RSK2 is required for IFNγ expression, because knockdown of RSK2 expression or overexpression of mutant T-bet reduces IFNγ mRNA expression. To verify the function of the phosphorylation sites, we overexpressed a constitutively active mutant T-bet (S498E/S502E) in bone marrow. Mutant T-bet restored the IFNγ mRNA levels and dramatically reduced the metastasis rate in these mice. Overall, these results indicate that phosphorylation of T-bet is required for the inhibition of colon cancer metastasis and growth through a positive regulation of RSK2/T-bet/IFNγ signaling.

scholarly journals Stable RNA interference of hexokinase II gene inhibits human colon cancer LoVo cell growth in vitro and in vivo

2008 ◽  
Vol 7 (7) ◽  
pp. 1128-1135 ◽  
Author(s):  
Qiuping Peng ◽  
Qi Zhou ◽  
Daping Zhong ◽  
Feng Pan ◽  
Houjie Liang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Rna Interference ◽  
Cell Growth ◽  
Human Colon ◽  
Lovo Cell ◽  
Hexokinase Ii ◽  
Human Colon Cancer

scholarly journals Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p

2020 ◽  
Author(s):  
Shiue-Wei Lai ◽  
Ming-Yao Chen ◽  
Ming-Shou Hsieh ◽  
Ting-Yi Huang ◽  
Chi-Tai Yeh ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Growth Factor ◽  
Cell Lines ◽  
Distant Metastasis ◽  
Colony Formation ◽  
Cancer Metastasis ◽  
Lovo Cell ◽  
Promoting Effect

Abstract Background: Late-stage colon cancer remains a treatment challenge in clinical settings because of the development of drug resistance and distant metastasis. Nevertheless, the mechanisms through which colon cancer cells acquire the ability to metastasize are complicated and require more research.Methods: Bioinformatic analysis was performed to determine gene associated with exosomal lncRNA PVT1/VEGFA axis of colon cancer patients. Biological importance of exosomal lncRNA PVT1/VEGFA axis was investigated in vitro (HCT116 and LoVo cell lines) and in vivo (PDX mouse model) through knockdown (siPVT1) and overexpression (add exosomes from sera of distant metastasis patients). PVT1/VEGFA axis related protein expression in and cell lines were investigated through RT-qPCR, immunoblotting, and immunohistochemistry analysis. Colony formation Assay, cell invasion, migration, and tumorsphere-formation assay were used to explore possible molecular mechanism. Results: First, using public databases, we demonstrated that PVT1 overexpression is associated with poor prognosis and increased metastatic markers, such as vascular endothelial growth factor A (VEGFA) and epidermal growth factor receptor (EGFR). This finding was then validated in a small cohort of patients with colon cancer, where increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. Notably, serum exosomes from patients with metastatic (M-exo) colon cancer were enriched with PVT1 and VEGFA and increased both migratory and invasive abilities in colon cancer cell lines when cocultured. This metastasis-promoting effect was accompanied by an increased expression of Twist1, Vimentin, and MMP2. Notably, M-exo promoted metastatic incidence in patient-derived xenograft mice. In vitro silencing of PVT1 led to decreased colon tumorigenic properties, including colony formation, tumorsphere formation, and metastatic potential. Further analysis revealed that miR-152-3p has multiple targets, including PVT1, VEGFA, and EGFR. Increased miR-152-3p resulted in decreased tumorigenesis, and the reverse was true when the miR-152-3p level was decreased.Conclusion: In conclusion, we provided evidence regarding the role of exosomal PVT1 in promoting metastasis in colon cancer through its association with EGFR and VEGFA expression. PVT1 and VEGFA are both targets of miR-152-3p, and this regulatory pathway could be explored for drug and prognostic biomarker development.

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