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MicroRNA-192 suppresses liver metastasis of colon cancer.

Geng L, Chaudhuri A, Talmon G, Wisecarver JL, Are C, Brattain M, Wang J - Oncogene (2013)

Bottom Line: Alterations associated with the metastatic phenotype in the primary tumors include increased apoptosis, decreased proliferation and angiogenesis.Finally, studies performed on human colonic adenocarcinoma show that expression of miR-192 is significantly reduced in neoplastic cells as compared with normal colonic epithelium.Importantly, there is a significant decrease in miR-192 expression in stage IV tumors when compared with stage I or II lesions.

View Article: PubMed Central - PubMed

Affiliation: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE, USA.

ABSTRACT
Metastasis causes most deaths from colon cancer yet mechanistic understanding and therapeutic options remain limited. Here we show that expression of microRNA (miR)-192 is inversely correlated with metastatic potential of colon cancer cells. Ectopic expression of miR-192 sensitizes colon cancer cells to growth factor deprivation stress-induced apoptosis, whereas inhibition of miR-192 confers resistance. Overexpression of miR-192 inhibits metastatic colonization to the liver in an orthotopic mouse model of colon cancer. Alterations associated with the metastatic phenotype in the primary tumors include increased apoptosis, decreased proliferation and angiogenesis. Further studies indicate that miR-192 downregulates expression of Bcl-2, Zeb2 and VEGFA in vitro and in vivo, which is responsible for enhanced apoptosis, increased expression of E-cadherin and decreased angiogenesis in vivo, respectively. Finally, studies performed on human colonic adenocarcinoma show that expression of miR-192 is significantly reduced in neoplastic cells as compared with normal colonic epithelium. Importantly, there is a significant decrease in miR-192 expression in stage IV tumors when compared with stage I or II lesions. These findings indicate that miR-192 has an important role in colon cancer development and progression. Our studies underscore the clinical relevance and prognostic significance of miR-192 expression in colon cancer. Therefore, a major implication of our studies is that restoration of miR-192 expression or antagonism of its target genes (Bcl-2, Zeb2 or VEGFA) may have considerable therapeutic potential for anti-metastatic therapy in patients with colon cancer.

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Expression of miR-192 in human colon cancer cell lines determined by real-time Q-PCRA, Expression of miR-192 in FET cells treated with TGFβ for indicated time periods. B, Expression of miR-192 in colon cancer cell lines with different metastatic potential. Values represent the means ± SE of triplicate Q-PCR values from a representative experiment performed at least three times.
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Figure 1: Expression of miR-192 in human colon cancer cell lines determined by real-time Q-PCRA, Expression of miR-192 in FET cells treated with TGFβ for indicated time periods. B, Expression of miR-192 in colon cancer cell lines with different metastatic potential. Values represent the means ± SE of triplicate Q-PCR values from a representative experiment performed at least three times.

Mentions: It has been previously reported that TGFβ signaling mediates metastasis in colon cancer cells (19;20). To identify miRNAs that affect colon cancer metastasis, we search for miRNAs whose expression is regulated by TGFβ signaling. Expression of miR-192 has been shown to be induced by TGFβ in mouse glomerular mesangial cells (21) and down-regulated in colon cancer tissue samples (22;23). When TGFβ-responsive colon cancer FET cells were treated with TGFβ, expression of miR-192 was induced in a time-dependent manner (Fig. 1A). Given the function of TGFβ in colon cancer metastasis, these results suggest that miR-192 might play a role in colon cancer metastasis as well.


MicroRNA-192 suppresses liver metastasis of colon cancer.

Geng L, Chaudhuri A, Talmon G, Wisecarver JL, Are C, Brattain M, Wang J - Oncogene (2013)

Expression of miR-192 in human colon cancer cell lines determined by real-time Q-PCRA, Expression of miR-192 in FET cells treated with TGFβ for indicated time periods. B, Expression of miR-192 in colon cancer cell lines with different metastatic potential. Values represent the means ± SE of triplicate Q-PCR values from a representative experiment performed at least three times.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4016997&req=5

Figure 1: Expression of miR-192 in human colon cancer cell lines determined by real-time Q-PCRA, Expression of miR-192 in FET cells treated with TGFβ for indicated time periods. B, Expression of miR-192 in colon cancer cell lines with different metastatic potential. Values represent the means ± SE of triplicate Q-PCR values from a representative experiment performed at least three times.
Mentions: It has been previously reported that TGFβ signaling mediates metastasis in colon cancer cells (19;20). To identify miRNAs that affect colon cancer metastasis, we search for miRNAs whose expression is regulated by TGFβ signaling. Expression of miR-192 has been shown to be induced by TGFβ in mouse glomerular mesangial cells (21) and down-regulated in colon cancer tissue samples (22;23). When TGFβ-responsive colon cancer FET cells were treated with TGFβ, expression of miR-192 was induced in a time-dependent manner (Fig. 1A). Given the function of TGFβ in colon cancer metastasis, these results suggest that miR-192 might play a role in colon cancer metastasis as well.

Bottom Line: Alterations associated with the metastatic phenotype in the primary tumors include increased apoptosis, decreased proliferation and angiogenesis.Finally, studies performed on human colonic adenocarcinoma show that expression of miR-192 is significantly reduced in neoplastic cells as compared with normal colonic epithelium.Importantly, there is a significant decrease in miR-192 expression in stage IV tumors when compared with stage I or II lesions.

View Article: PubMed Central - PubMed

Affiliation: Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE, USA.

ABSTRACT
Metastasis causes most deaths from colon cancer yet mechanistic understanding and therapeutic options remain limited. Here we show that expression of microRNA (miR)-192 is inversely correlated with metastatic potential of colon cancer cells. Ectopic expression of miR-192 sensitizes colon cancer cells to growth factor deprivation stress-induced apoptosis, whereas inhibition of miR-192 confers resistance. Overexpression of miR-192 inhibits metastatic colonization to the liver in an orthotopic mouse model of colon cancer. Alterations associated with the metastatic phenotype in the primary tumors include increased apoptosis, decreased proliferation and angiogenesis. Further studies indicate that miR-192 downregulates expression of Bcl-2, Zeb2 and VEGFA in vitro and in vivo, which is responsible for enhanced apoptosis, increased expression of E-cadherin and decreased angiogenesis in vivo, respectively. Finally, studies performed on human colonic adenocarcinoma show that expression of miR-192 is significantly reduced in neoplastic cells as compared with normal colonic epithelium. Importantly, there is a significant decrease in miR-192 expression in stage IV tumors when compared with stage I or II lesions. These findings indicate that miR-192 has an important role in colon cancer development and progression. Our studies underscore the clinical relevance and prognostic significance of miR-192 expression in colon cancer. Therefore, a major implication of our studies is that restoration of miR-192 expression or antagonism of its target genes (Bcl-2, Zeb2 or VEGFA) may have considerable therapeutic potential for anti-metastatic therapy in patients with colon cancer.

Show MeSH
Related in: MedlinePlus