Limits...
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.

Show MeSH

Related in: MedlinePlus

miR-192 inhibits expression of its target genes in vivoImages of IHC staining of Bcl2 (A), VEGFA (B), Zeb2 (C) and E-cadherin (D) in primary tumors are shown in the upper panels. Staining density was measured and quantified as described in Materials and Methods. The data are presented as the mean ± SE. * P < 0.001 (lower panels).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4016997&req=5

Figure 5: miR-192 inhibits expression of its target genes in vivoImages of IHC staining of Bcl2 (A), VEGFA (B), Zeb2 (C) and E-cadherin (D) in primary tumors are shown in the upper panels. Staining density was measured and quantified as described in Materials and Methods. The data are presented as the mean ± SE. * P < 0.001 (lower panels).

Mentions: To determine whether miR-192 represses expression of Bcl-2, Zeb2 or VEGFA in vivo, we examined their expression in the primary tumors of mice implanted with vector- or miR-192-expressing HCT116 cells described above. IHC staining revealed that expression of Bcl-2 and VEGFA was significantly reduced in the primary tumors of miR-192-expressing cells as compared to those of the control cells (Fig. 5A & 5B, *P < 0.001), which likely contributes to the differences observed in apoptosis (TUNEL, Fig. 3C) and angiogenesis (CD31, Fig. 3E) respectively between these two groups. In addition, a remarkable reduction of Zeb2 expression, especially in the nucleus, was also detected in the primary tumors of miR-192 cells when compared to the control tumors (Fig. 5C, *P < 0.001). Consequently, an increase of membrane expression of E-cadherin was observed in those tumors (Fig. 5D, *P < 0.001). These results indicate that miR-192 inhibits expression of Bcl-2, VEGFA and Zeb2 in the primary tumors, combination of which contributes to diminished liver metastasis in the orthotopic model.


MicroRNA-192 suppresses liver metastasis of colon cancer.

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

miR-192 inhibits expression of its target genes in vivoImages of IHC staining of Bcl2 (A), VEGFA (B), Zeb2 (C) and E-cadherin (D) in primary tumors are shown in the upper panels. Staining density was measured and quantified as described in Materials and Methods. The data are presented as the mean ± SE. * P < 0.001 (lower panels).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: miR-192 inhibits expression of its target genes in vivoImages of IHC staining of Bcl2 (A), VEGFA (B), Zeb2 (C) and E-cadherin (D) in primary tumors are shown in the upper panels. Staining density was measured and quantified as described in Materials and Methods. The data are presented as the mean ± SE. * P < 0.001 (lower panels).
Mentions: To determine whether miR-192 represses expression of Bcl-2, Zeb2 or VEGFA in vivo, we examined their expression in the primary tumors of mice implanted with vector- or miR-192-expressing HCT116 cells described above. IHC staining revealed that expression of Bcl-2 and VEGFA was significantly reduced in the primary tumors of miR-192-expressing cells as compared to those of the control cells (Fig. 5A & 5B, *P < 0.001), which likely contributes to the differences observed in apoptosis (TUNEL, Fig. 3C) and angiogenesis (CD31, Fig. 3E) respectively between these two groups. In addition, a remarkable reduction of Zeb2 expression, especially in the nucleus, was also detected in the primary tumors of miR-192 cells when compared to the control tumors (Fig. 5C, *P < 0.001). Consequently, an increase of membrane expression of E-cadherin was observed in those tumors (Fig. 5D, *P < 0.001). These results indicate that miR-192 inhibits expression of Bcl-2, VEGFA and Zeb2 in the primary tumors, combination of which contributes to diminished liver metastasis in the orthotopic model.

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