Limits...
MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

Ogawa H, Wu X, Kawamoto K, Nishida N, Konno M, Koseki J, Matsui H, Noguchi K, Gotoh N, Yamamoto T, Miyata K, Nishiyama N, Nagano H, Yamamoto H, Obika S, Kataoka K, Doki Y, Mori M, Ishii H - PLoS ONE (2015)

Bottom Line: Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy.This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells.Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

ABSTRACT
Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR) 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors.

No MeSH data available.


Related in: MedlinePlus

miR distribution and adverse effects of systemic administration.A) Relative expression of miR-302s in xenografts 24 h after intravenous injection with miR-302s two or three times daily. NTERA was used as a positive control for miR-302s. Mean expression of each miR was compared with that of the negative control (NC) miR group (n = 3). B) Relative expression of miR-302s and miR-369s in xenografts treated with miR-302s plus miR-369s, NC miR, or the mock control. Tumors were harvested 3 d after injection of the indicated miRs on 14 consecutive days. Mean expression was compared with that in the mock treatment (n = 3). C) Mean values of biochemical parameters in the serum of mice treated with 14 consecutive daily injections of miR-302s plus miR-369s or NC miR (n = 4). D) Monitoring of the body weight of mice treated with 14 consecutive daily injections of miR-302s plus miR-369s, NC miR, or the mock control(n = 4). E) Representative images of hematoxylin and eosin staining of the liver, kidney and spleen from mice treated with 14 consecutive daily injections of miR-302s plus miR-369s or the mock control. Scale bars, 200 μm. Asterisk denotes a p-value in the Student t-test of < 0.05 (mean ± s.e.m.).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4430240&req=5

pone.0127119.g010: miR distribution and adverse effects of systemic administration.A) Relative expression of miR-302s in xenografts 24 h after intravenous injection with miR-302s two or three times daily. NTERA was used as a positive control for miR-302s. Mean expression of each miR was compared with that of the negative control (NC) miR group (n = 3). B) Relative expression of miR-302s and miR-369s in xenografts treated with miR-302s plus miR-369s, NC miR, or the mock control. Tumors were harvested 3 d after injection of the indicated miRs on 14 consecutive days. Mean expression was compared with that in the mock treatment (n = 3). C) Mean values of biochemical parameters in the serum of mice treated with 14 consecutive daily injections of miR-302s plus miR-369s or NC miR (n = 4). D) Monitoring of the body weight of mice treated with 14 consecutive daily injections of miR-302s plus miR-369s, NC miR, or the mock control(n = 4). E) Representative images of hematoxylin and eosin staining of the liver, kidney and spleen from mice treated with 14 consecutive daily injections of miR-302s plus miR-369s or the mock control. Scale bars, 200 μm. Asterisk denotes a p-value in the Student t-test of < 0.05 (mean ± s.e.m.).

Mentions: We performed qRT-PCR to investigate whether systemic administration of miRs was distributed into the deep areas of tumors. The data indicated that systemic administration of miRs led to excellent distribution in xenografts (Fig 10A and 10B). Although systemic administrations of miR-302s plus miR-369s were repeated for 14 consecutive days, we did not detect any noticeable adverse effects in laboratory blood tests, body weight or histology of the liver, kidney and spleen (Fig 10C, 10D and 10E).


MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

Ogawa H, Wu X, Kawamoto K, Nishida N, Konno M, Koseki J, Matsui H, Noguchi K, Gotoh N, Yamamoto T, Miyata K, Nishiyama N, Nagano H, Yamamoto H, Obika S, Kataoka K, Doki Y, Mori M, Ishii H - PLoS ONE (2015)

miR distribution and adverse effects of systemic administration.A) Relative expression of miR-302s in xenografts 24 h after intravenous injection with miR-302s two or three times daily. NTERA was used as a positive control for miR-302s. Mean expression of each miR was compared with that of the negative control (NC) miR group (n = 3). B) Relative expression of miR-302s and miR-369s in xenografts treated with miR-302s plus miR-369s, NC miR, or the mock control. Tumors were harvested 3 d after injection of the indicated miRs on 14 consecutive days. Mean expression was compared with that in the mock treatment (n = 3). C) Mean values of biochemical parameters in the serum of mice treated with 14 consecutive daily injections of miR-302s plus miR-369s or NC miR (n = 4). D) Monitoring of the body weight of mice treated with 14 consecutive daily injections of miR-302s plus miR-369s, NC miR, or the mock control(n = 4). E) Representative images of hematoxylin and eosin staining of the liver, kidney and spleen from mice treated with 14 consecutive daily injections of miR-302s plus miR-369s or the mock control. Scale bars, 200 μm. Asterisk denotes a p-value in the Student t-test of < 0.05 (mean ± s.e.m.).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430240&req=5

pone.0127119.g010: miR distribution and adverse effects of systemic administration.A) Relative expression of miR-302s in xenografts 24 h after intravenous injection with miR-302s two or three times daily. NTERA was used as a positive control for miR-302s. Mean expression of each miR was compared with that of the negative control (NC) miR group (n = 3). B) Relative expression of miR-302s and miR-369s in xenografts treated with miR-302s plus miR-369s, NC miR, or the mock control. Tumors were harvested 3 d after injection of the indicated miRs on 14 consecutive days. Mean expression was compared with that in the mock treatment (n = 3). C) Mean values of biochemical parameters in the serum of mice treated with 14 consecutive daily injections of miR-302s plus miR-369s or NC miR (n = 4). D) Monitoring of the body weight of mice treated with 14 consecutive daily injections of miR-302s plus miR-369s, NC miR, or the mock control(n = 4). E) Representative images of hematoxylin and eosin staining of the liver, kidney and spleen from mice treated with 14 consecutive daily injections of miR-302s plus miR-369s or the mock control. Scale bars, 200 μm. Asterisk denotes a p-value in the Student t-test of < 0.05 (mean ± s.e.m.).
Mentions: We performed qRT-PCR to investigate whether systemic administration of miRs was distributed into the deep areas of tumors. The data indicated that systemic administration of miRs led to excellent distribution in xenografts (Fig 10A and 10B). Although systemic administrations of miR-302s plus miR-369s were repeated for 14 consecutive days, we did not detect any noticeable adverse effects in laboratory blood tests, body weight or histology of the liver, kidney and spleen (Fig 10C, 10D and 10E).

Bottom Line: Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy.This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells.Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

ABSTRACT
Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR) 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors.

No MeSH data available.


Related in: MedlinePlus