Abstract
The self-renewal capacity ascribed to embryonic stem cells (ESC) is reminiscent of cancer cell proliferation, raising speculation that a common network of genes may regulate these traits. A search for general regulators of these traits yielded a set of microRNAs for which expression is highly enriched in human ESCs and liver cancer cells (HCC) but attenuated in differentiated quiescent hepatocytes. Here, we show that these microRNAs promote hESC self-renewal, as well as HCC proliferation, and when overexpressed in normally quiescent hepatocytes, induce proliferation and activate cancer signaling pathways. Proliferation in hepatocytes is mediated through translational repression of Pten, Tgfbr2, Klf11, and Cdkn1a, which collectively dysregulates the PI3K/AKT/mTOR and TGFβ tumor suppressor signaling pathways. Furthermore, aberrant expression of these miRNAs is observed in human liver tumor tissues and induces epithelial - mesenchymal transition in hepatocytes. These findings suggest that microRNAs that are essential in normal development as promoters of ESC self-renewal are frequently upregulated in human liver tumors and harbor neoplastic transformation potential when they escape silencing in quiescent human hepatocytes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 979-991 |
| Number of pages | 13 |
| Journal | Molecular Cancer Research |
| Volume | 10 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2012 |
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ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Oncology
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Human ESC self-renewal promoting microRNAs induce epithelial - Mesenchymal transition in hepatocytes by controlling the PTEN and TGFβ tumor suppressor signaling pathways. / Jung, Christine J.; Iyengar, Sushma; Blahnik, Kimberly R.; Jiang, Xiaosong; Tahimic, Candice; Torok, Natalia J; deVere White, Ralph W; Farnham, Peggy J.; Zern, Mark A.
In: Molecular Cancer Research, Vol. 10, No. 7, 07.2012, p. 979-991.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Human ESC self-renewal promoting microRNAs induce epithelial - Mesenchymal transition in hepatocytes by controlling the PTEN and TGFβ tumor suppressor signaling pathways
AU - Jung, Christine J.
AU - Iyengar, Sushma
AU - Blahnik, Kimberly R.
AU - Jiang, Xiaosong
AU - Tahimic, Candice
AU - Torok, Natalia J
AU - deVere White, Ralph W
AU - Farnham, Peggy J.
AU - Zern, Mark A
PY - 2012/7
Y1 - 2012/7
N2 - The self-renewal capacity ascribed to embryonic stem cells (ESC) is reminiscent of cancer cell proliferation, raising speculation that a common network of genes may regulate these traits. A search for general regulators of these traits yielded a set of microRNAs for which expression is highly enriched in human ESCs and liver cancer cells (HCC) but attenuated in differentiated quiescent hepatocytes. Here, we show that these microRNAs promote hESC self-renewal, as well as HCC proliferation, and when overexpressed in normally quiescent hepatocytes, induce proliferation and activate cancer signaling pathways. Proliferation in hepatocytes is mediated through translational repression of Pten, Tgfbr2, Klf11, and Cdkn1a, which collectively dysregulates the PI3K/AKT/mTOR and TGFβ tumor suppressor signaling pathways. Furthermore, aberrant expression of these miRNAs is observed in human liver tumor tissues and induces epithelial - mesenchymal transition in hepatocytes. These findings suggest that microRNAs that are essential in normal development as promoters of ESC self-renewal are frequently upregulated in human liver tumors and harbor neoplastic transformation potential when they escape silencing in quiescent human hepatocytes.
AB - The self-renewal capacity ascribed to embryonic stem cells (ESC) is reminiscent of cancer cell proliferation, raising speculation that a common network of genes may regulate these traits. A search for general regulators of these traits yielded a set of microRNAs for which expression is highly enriched in human ESCs and liver cancer cells (HCC) but attenuated in differentiated quiescent hepatocytes. Here, we show that these microRNAs promote hESC self-renewal, as well as HCC proliferation, and when overexpressed in normally quiescent hepatocytes, induce proliferation and activate cancer signaling pathways. Proliferation in hepatocytes is mediated through translational repression of Pten, Tgfbr2, Klf11, and Cdkn1a, which collectively dysregulates the PI3K/AKT/mTOR and TGFβ tumor suppressor signaling pathways. Furthermore, aberrant expression of these miRNAs is observed in human liver tumor tissues and induces epithelial - mesenchymal transition in hepatocytes. These findings suggest that microRNAs that are essential in normal development as promoters of ESC self-renewal are frequently upregulated in human liver tumors and harbor neoplastic transformation potential when they escape silencing in quiescent human hepatocytes.
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U2 - 10.1158/1541-7786.MCR-11-0421
DO - 10.1158/1541-7786.MCR-11-0421
M3 - Article
C2 - 22622027
AN - SCOPUS:84864009582
VL - 10
SP - 979
EP - 991
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 7
ER -