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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-101 efficiently inhibits c-Myc and AKT/Ras induced liver tumor development(A) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from c-Myc/pT3 mice and c-Myc/miR-101 mice stained with H&E (100X), insets (400 X). (B) Kaplan Meier survival curve of c-Myc/pT3 and c-Myc/miR-101 mouse cohort. (C) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from AKT/Ras/PT3 mice and AKT/Ras/miR-101 mice stained with H&E (100X). (D) Kaplan Meier survival curve of AKT/Ras/pT3 and AKT/Ras/miR-101 mouse cohort.
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Figure 5: Overexpression of miR-101 efficiently inhibits c-Myc and AKT/Ras induced liver tumor development(A) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from c-Myc/pT3 mice and c-Myc/miR-101 mice stained with H&E (100X), insets (400 X). (B) Kaplan Meier survival curve of c-Myc/pT3 and c-Myc/miR-101 mouse cohort. (C) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from AKT/Ras/PT3 mice and AKT/Ras/miR-101 mice stained with H&E (100X). (D) Kaplan Meier survival curve of AKT/Ras/pT3 and AKT/Ras/miR-101 mouse cohort.

Mentions: Different from all the other tumor suppressor miRNAs tested, overexpression of miR-101 completely prevented both c-Myc and AKT/Ras driven liver tumor formation in mice. Specifically, all c-Myc/miR-101 injected mice appear to be healthy 8 weeks post injection (Figure 5A and 5B). Upon dissection, no liver tumor nodules were identified, and livers of c-Myc/miR-101 injected mice appeared to be completely normal histologically (Figure 5A). Similarly, none of the AKT/Ras/miR-101 injected mice showed any sign of tumor development at the same time point (Figure 5C and 5D). Livers from AKT/Ras/miR-101 injected mice were slightly pale, and clusters of lipid-rich preneoplastic hepatocytes were detected at the microscopic level (Figure 5A).


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-101 efficiently inhibits c-Myc and AKT/Ras induced liver tumor development(A) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from c-Myc/pT3 mice and c-Myc/miR-101 mice stained with H&E (100X), insets (400 X). (B) Kaplan Meier survival curve of c-Myc/pT3 and c-Myc/miR-101 mouse cohort. (C) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from AKT/Ras/PT3 mice and AKT/Ras/miR-101 mice stained with H&E (100X). (D) Kaplan Meier survival curve of AKT/Ras/pT3 and AKT/Ras/miR-101 mouse cohort.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466663&req=5

Figure 5: Overexpression of miR-101 efficiently inhibits c-Myc and AKT/Ras induced liver tumor development(A) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from c-Myc/pT3 mice and c-Myc/miR-101 mice stained with H&E (100X), insets (400 X). (B) Kaplan Meier survival curve of c-Myc/pT3 and c-Myc/miR-101 mouse cohort. (C) Macroscopic (upper panel) and microscopic (lower panel) appearance of livers from AKT/Ras/PT3 mice and AKT/Ras/miR-101 mice stained with H&E (100X). (D) Kaplan Meier survival curve of AKT/Ras/pT3 and AKT/Ras/miR-101 mouse cohort.
Mentions: Different from all the other tumor suppressor miRNAs tested, overexpression of miR-101 completely prevented both c-Myc and AKT/Ras driven liver tumor formation in mice. Specifically, all c-Myc/miR-101 injected mice appear to be healthy 8 weeks post injection (Figure 5A and 5B). Upon dissection, no liver tumor nodules were identified, and livers of c-Myc/miR-101 injected mice appeared to be completely normal histologically (Figure 5A). Similarly, none of the AKT/Ras/miR-101 injected mice showed any sign of tumor development at the same time point (Figure 5C and 5D). Livers from AKT/Ras/miR-101 injected mice were slightly pale, and clusters of lipid-rich preneoplastic hepatocytes were detected at the microscopic level (Figure 5A).

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