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

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.

Download Full-text

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

Journal of Surgical Research ◽

10.1016/j.jss.2004.07.109 ◽

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

Download Full-text

ACLY facilitates colon cancer cell metastasis by CTNNB1

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1391-9 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 12

Author(s):

Jun Wen ◽

Xuejie Min ◽

Mengqin Shen ◽

Qian Hua ◽

Yuan Han ◽

...

Keyword(s):

Colon Cancer ◽

Cell Migration ◽

Cancer Patients ◽

Cancer Metastasis ◽

Colon Cancer Cell ◽

Migration And Invasion ◽

Colon Cancer Metastasis ◽

Invasion Assays

Abstract Background Colon cancer is the second leading cancer worldwide. Recurrent disease and chemotherapeutic drug resistance are very common in the advanced stage of colon cancer. ATP-citrate lyase (ACLY), the first-step rate-controlling enzyme in lipid synthesis, is elevated in colon cancer. However, it remains unclear about the exact role of ACLY in the development of colon cancer metastasis. Methods To evaluate the role of ACLY in colon cancer metastasis, we performed cell migration and invasion assays in two ACLY-deficient colon cancer cell lines. Colon cancer mouse model is used to examine ACLY’s effects on colon metastasis potentials in vivo. We analyzed the correlation between ACLY and CTNNB1 protein in 78 colon cancer patients by Pearson correlation. To finally explore the relationship of ACLY and CTNNB1, we used western blots, migration and invasion assays to confirm that ACLY may regulate metastasis by CTNNB1. Results Our data showed that the abilities of cell migration and invasion were attenuated in ACLY-deficient HCT116 and RKO cell lines. Furthermore, we describe the mechanism of ACLY in promoting colon cancer metastasis in vitro and in vivo. ACLY could stabilize CTNNB1 (beta-catenin 1) protein by interacting, and the complex might promote CTNNB1 translocation through cytoplasm to nucleus, subsequently promote the CTNNB1 transcriptional activity and migration and invasion abilities of colon cancer cells. Immunohistochemical analysis of 78 colon cancer patients showed that the high expression levels of ACLY and CTNNB1 protein was positively correlated with metastasis of colon cancer. Conclusions These results shed new light on the molecular mechanism underlying colon cancer metastasis, which might help in improving therapeutic efficacy.

Download Full-text

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

Scientific Reports ◽

10.1038/s41598-020-80911-z ◽

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.

Download Full-text

Oxidative stress promotes liver cancer metastasis via a PKA-activated RNF25/ECAD/YAP circuit

10.21203/rs.3.rs-1197819/v1 ◽

2022 ◽

Author(s):

Zhao Huang ◽

Li Zhou ◽

Jiufei Duan ◽

Siyuan Qin ◽

Yu Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Cancer Metastasis ◽

Anoikis Resistance ◽

Antioxidant Genes ◽

Redox Sensor ◽

Stress Signals ◽

Hcc Cells

Abstract Loss of E-cadherin (ECAD), often caused by epigenetic inactivation, is closely associated with tumor metastasis. However, how ECAD is regulated in response to oxidative stress during tumorigenesis is largely unknown. Here we identify RNF25 as a new E3 ligase of ECAD, whose activation by oxidative stress leads to ECAD protein degradation in hepatocellular carcinoma (HCC). Loss of ECAD activates YAP, which in turn promotes the transcription of RNF25, thus forming a positive feedback loop to sustain the ECAD downregulation. YAP activation mitigates oxidative stress in detached HCC cells by upregulating antioxidant genes, protecting detached HCC cells from ferroptosis, resulting in anoikis resistance. Mechanistically, we found that protein kinase A (PKA) senses oxidative stress by redox modification in its β catalytic subunit (PRKACB) at Cys200 and Cys344, which increases its kinase activity towards RNF25 phosphorylation at Ser450, facilitating RNF25-mediated degradation of ECAD. Moreover, RNF25 expression is associated with HCC metastasis and depletion of RNF25 is sufficient to diminish HCC invasion and metastasis in vitro and in vivo. Together, these results identify a dual role of RNF25 as a critical regulator of ECAD protein turnover, promoting both anoikis resistance and metastasis, and PKA is a necessary redox sensor to enable this process. Our study provides mechanistic insight into how tumor cells sense oxidative stress signals to spread while escaping cell death.

Download Full-text

A critical role of CCR7 in invasiveness and metastasis of SW620 colon cancer cell in vitro and in vivo

Cancer Biology & Therapy ◽

10.4161/cbt.7.7.6065 ◽

2008 ◽

Vol 7 (7) ◽

pp. 1037-1043 ◽

Cited By ~ 15

Author(s):

Yu Shuyi ◽

Duan Juping ◽

Zhou Zhiqun ◽

Pang Qiong ◽

Ji Wuyang ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cell ◽

Critical Role ◽

Colon Cancer Cell

Download Full-text

Potential of Lunasin Orally-Administered in Comparison to Intraperitoneal Injection to Inhibit Colon Cancer Metastasis <i>in Vivo</i>

Journal of Cancer Therapy ◽

10.4236/jct.2013.46a2005 ◽

2013 ◽

Vol 04 (06) ◽

pp. 34-43 ◽

Cited By ~ 9

Author(s):

Vermont P. Dia ◽

Elvira Gonzalez de Mejia

Keyword(s):

Colon Cancer ◽

Intraperitoneal Injection ◽

Cancer Metastasis ◽

Colon Cancer Metastasis

Download Full-text

Genistein represses invasion in an in vitro colon cancer metastasis model by transcriptionally upregulating metastasis repressor NDRG1

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.116.6 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Qian Li ◽

Hong Chen

Keyword(s):

Colon Cancer ◽

Cancer Metastasis ◽

Colon Cancer Metastasis ◽

Metastasis Model

Download Full-text

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.642930 ◽

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.

Download Full-text