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Distinct anti-oncogenic effect of various microRNAs in different mouse models of liver cancer.

Tao J, Ji J, Li X, Ding N, Wu H, Liu Y, Wang XW, Calvisi DF, Song G, Chen X - Oncotarget (2015)

Bottom Line: Noticeably, miR-375 showed limited antineoplastic activity against c-Myc driven tumorigenesis, whereas it strongly inhibited AKT/Ras induced hepatocarcinogenesis.Furthermore, miR-101 significantly suppressed both c-Myc and AKT/Ras liver tumor development.Altogether, the present data demonstrate that different oncogenes induce distinct miRNA patterns, whose modulation differently affects hepatocarcinogenesis depending on the driving oncogenes.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.

ABSTRACT
Deregulation of microRNAs (miRNAs) is a typical feature of human hepatocellular carcinoma (HCC). However, the in vivo relevance of miRNAs along hepatocarcinogenesis remains largely unknown. Here, we show that liver tumors induced in mice by c-Myc overexpression or AKT/Ras co-expression exhibit distinct miRNA expression profiles. Among the downregulated miRNAs, eight (miR-101, miR-107, miR-122, miR-29, miR-365, miR-375, miR-378, and miR-802) were selected and their tumor suppressor activity was determined by overexpressing each of them together with c-Myc or AKT/Ras oncogenes in mouse livers via hydrodynamic transfection. The tumor suppressor activity of these microRNAs was extremely heterogeneous in c-Myc and AKT/Ras mice: while miR-378 had no tumor suppressor activity, miR-107, mir-122, miR-29, miR-365 and miR-802 exhibited weak to moderate tumor suppressor potential. Noticeably, miR-375 showed limited antineoplastic activity against c-Myc driven tumorigenesis, whereas it strongly inhibited AKT/Ras induced hepatocarcinogenesis. Furthermore, miR-101 significantly suppressed both c-Myc and AKT/Ras liver tumor development. Altogether, the present data demonstrate that different oncogenes induce distinct miRNA patterns, whose modulation differently affects hepatocarcinogenesis depending on the driving oncogenes. Finally, our findings support a strong tumor suppressor activity of miR-101 in liver cancer models regardless of the driver oncogenes involved, thus representing a promising therapeutic target in human HCC.

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Overexpression of miR-375 strongly inhibits AKT/Ras but not c-Myc induced liver tumor formation in mice(A) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from c-Myc/pT3 mice and c-Myc/miR-375 mice stained with H&E (100X), insets (400X). (B) Kaplan Meier survival curve of c-Myc/pT3 and c-Myc/miR-375 mouse cohort. (C) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from AKT/Ras/PT3 mice and AKT/Ras/miR-375 mice stained with H&E (100X). (D) Kaplan Meier survival curve of AKT/Ras/pT3 and AKT/Ras/miR-375 mouse cohort.
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Figure 4: Overexpression of miR-375 strongly inhibits AKT/Ras but not c-Myc induced liver tumor formation in mice(A) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from c-Myc/pT3 mice and c-Myc/miR-375 mice stained with H&E (100X), insets (400X). (B) Kaplan Meier survival curve of c-Myc/pT3 and c-Myc/miR-375 mouse cohort. (C) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from AKT/Ras/PT3 mice and AKT/Ras/miR-375 mice stained with H&E (100X). (D) Kaplan Meier survival curve of AKT/Ras/pT3 and AKT/Ras/miR-375 mouse cohort.

Mentions: Overexpression of miR-375 slightly delayed c-Myc induced liver tumor formation (Figure 4A and 4B). By 8 weeks post injection, all c-Myc/miR-375 injected mice succumbed due to the high tumor burden (Figure 4B). In striking contrast, miR-375 exhibited a strong tumor suppressor activity against AKT/Ras driven tumor development (Figure 4C and 4D). Indeed, none of the AKT/Ras/miR-375 injected mice showed any sign of tumor development 8 weeks post injection. Macroscopically, liver appeared to be normal (Figure 4C), while microscopically few, small clusters of lipid-rich preneoplastic hepatocytes were detected. Thus, the present findings support a strong tumor suppressive role of miR-375 against AKT/Ras driven hepatocarcinogenesis and a limited antineoplastic activity toward c-Myc induced liver tumor formation.


Distinct anti-oncogenic effect of various microRNAs in different mouse models of liver cancer.

Tao J, Ji J, Li X, Ding N, Wu H, Liu Y, Wang XW, Calvisi DF, Song G, Chen X - Oncotarget (2015)

Overexpression of miR-375 strongly inhibits AKT/Ras but not c-Myc induced liver tumor formation in mice(A) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from c-Myc/pT3 mice and c-Myc/miR-375 mice stained with H&E (100X), insets (400X). (B) Kaplan Meier survival curve of c-Myc/pT3 and c-Myc/miR-375 mouse cohort. (C) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from AKT/Ras/PT3 mice and AKT/Ras/miR-375 mice stained with H&E (100X). (D) Kaplan Meier survival curve of AKT/Ras/pT3 and AKT/Ras/miR-375 mouse cohort.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Overexpression of miR-375 strongly inhibits AKT/Ras but not c-Myc induced liver tumor formation in mice(A) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from c-Myc/pT3 mice and c-Myc/miR-375 mice stained with H&E (100X), insets (400X). (B) Kaplan Meier survival curve of c-Myc/pT3 and c-Myc/miR-375 mouse cohort. (C) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from AKT/Ras/PT3 mice and AKT/Ras/miR-375 mice stained with H&E (100X). (D) Kaplan Meier survival curve of AKT/Ras/pT3 and AKT/Ras/miR-375 mouse cohort.
Mentions: Overexpression of miR-375 slightly delayed c-Myc induced liver tumor formation (Figure 4A and 4B). By 8 weeks post injection, all c-Myc/miR-375 injected mice succumbed due to the high tumor burden (Figure 4B). In striking contrast, miR-375 exhibited a strong tumor suppressor activity against AKT/Ras driven tumor development (Figure 4C and 4D). Indeed, none of the AKT/Ras/miR-375 injected mice showed any sign of tumor development 8 weeks post injection. Macroscopically, liver appeared to be normal (Figure 4C), while microscopically few, small clusters of lipid-rich preneoplastic hepatocytes were detected. Thus, the present findings support a strong tumor suppressive role of miR-375 against AKT/Ras driven hepatocarcinogenesis and a limited antineoplastic activity toward c-Myc induced liver tumor formation.

Bottom Line: Noticeably, miR-375 showed limited antineoplastic activity against c-Myc driven tumorigenesis, whereas it strongly inhibited AKT/Ras induced hepatocarcinogenesis.Furthermore, miR-101 significantly suppressed both c-Myc and AKT/Ras liver tumor development.Altogether, the present data demonstrate that different oncogenes induce distinct miRNA patterns, whose modulation differently affects hepatocarcinogenesis depending on the driving oncogenes.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.

ABSTRACT
Deregulation of microRNAs (miRNAs) is a typical feature of human hepatocellular carcinoma (HCC). However, the in vivo relevance of miRNAs along hepatocarcinogenesis remains largely unknown. Here, we show that liver tumors induced in mice by c-Myc overexpression or AKT/Ras co-expression exhibit distinct miRNA expression profiles. Among the downregulated miRNAs, eight (miR-101, miR-107, miR-122, miR-29, miR-365, miR-375, miR-378, and miR-802) were selected and their tumor suppressor activity was determined by overexpressing each of them together with c-Myc or AKT/Ras oncogenes in mouse livers via hydrodynamic transfection. The tumor suppressor activity of these microRNAs was extremely heterogeneous in c-Myc and AKT/Ras mice: while miR-378 had no tumor suppressor activity, miR-107, mir-122, miR-29, miR-365 and miR-802 exhibited weak to moderate tumor suppressor potential. Noticeably, miR-375 showed limited antineoplastic activity against c-Myc driven tumorigenesis, whereas it strongly inhibited AKT/Ras induced hepatocarcinogenesis. Furthermore, miR-101 significantly suppressed both c-Myc and AKT/Ras liver tumor development. Altogether, the present data demonstrate that different oncogenes induce distinct miRNA patterns, whose modulation differently affects hepatocarcinogenesis depending on the driving oncogenes. Finally, our findings support a strong tumor suppressor activity of miR-101 in liver cancer models regardless of the driver oncogenes involved, thus representing a promising therapeutic target in human HCC.

Show MeSH
Related in: MedlinePlus