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Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine.

Kishikawa T, Otsuka M, Tan PS, Ohno M, Sun X, Yoshikawa T, Shibata C, Takata A, Kojima K, Takehana K, Ohishi M, Ota S, Noyama T, Kondo Y, Sato M, Soga T, Hoshida Y, Koike K - Oncotarget (2015)

Bottom Line: Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib.Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib.These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

ABSTRACT
Reduced expression of microRNA122 (miR122), a liver-specific microRNA, is frequent in hepatocellular carcinoma (HCC). However, its biological significances remain poorly understood. Because deregulated amino acid levels in cancers can affect their biological behavior, we determined the amino acid levels in miR122-silenced mouse liver tissues, in which intracellular arginine levels were significantly increased. The increased intracellular arginine levels were through upregulation of the solute carrier family 7 (SLC7A1), a transporter of arginine and a direct target of miR122. Arginine is the substrate for nitric oxide (NO) synthetase, and intracellular NO levels were increased in miR122-silenced HCC cells, with increased resistance to sorafenib, a multikinase inhibitor. Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib. Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib. These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset.

No MeSH data available.


Related in: MedlinePlus

Changes in amino acid levels in liver tissues from miR122-silencedmiceResults of amino acid analyses of liver tissues from control andmiR122-silenced transgenic mice (n = 2 each).WT, control mice; miR122-silenced, miR122-silenced transgenic mice.
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Figure 1: Changes in amino acid levels in liver tissues from miR122-silencedmiceResults of amino acid analyses of liver tissues from control andmiR122-silenced transgenic mice (n = 2 each).WT, control mice; miR122-silenced, miR122-silenced transgenic mice.

Mentions: Recently, metabolomic profiling has revealed a number of perturbed metabolicpathways, including amino acids, in cancers [24, 25]. To determine thebiological effects of impaired miR122 function on amino acid levels, the latterwere comprehensively quantified in miR122-silenced mouse liver tissues [5]. Of the 20 amino acids examined, arginineshowed reproducible differences in levels in between the control andmiR122-silenced liver tissues from two individuals per group (Figure 1). Because arginine is an amino acid whichis transported into cells via SLC7A1 [26], a target of miR122, we focused on the reproducibly increasedarginine content of miR122-silenced tissues, in subsequent studies.


Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine.

Kishikawa T, Otsuka M, Tan PS, Ohno M, Sun X, Yoshikawa T, Shibata C, Takata A, Kojima K, Takehana K, Ohishi M, Ota S, Noyama T, Kondo Y, Sato M, Soga T, Hoshida Y, Koike K - Oncotarget (2015)

Changes in amino acid levels in liver tissues from miR122-silencedmiceResults of amino acid analyses of liver tissues from control andmiR122-silenced transgenic mice (n = 2 each).WT, control mice; miR122-silenced, miR122-silenced transgenic mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480756&req=5

Figure 1: Changes in amino acid levels in liver tissues from miR122-silencedmiceResults of amino acid analyses of liver tissues from control andmiR122-silenced transgenic mice (n = 2 each).WT, control mice; miR122-silenced, miR122-silenced transgenic mice.
Mentions: Recently, metabolomic profiling has revealed a number of perturbed metabolicpathways, including amino acids, in cancers [24, 25]. To determine thebiological effects of impaired miR122 function on amino acid levels, the latterwere comprehensively quantified in miR122-silenced mouse liver tissues [5]. Of the 20 amino acids examined, arginineshowed reproducible differences in levels in between the control andmiR122-silenced liver tissues from two individuals per group (Figure 1). Because arginine is an amino acid whichis transported into cells via SLC7A1 [26], a target of miR122, we focused on the reproducibly increasedarginine content of miR122-silenced tissues, in subsequent studies.

Bottom Line: Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib.Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib.These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

ABSTRACT
Reduced expression of microRNA122 (miR122), a liver-specific microRNA, is frequent in hepatocellular carcinoma (HCC). However, its biological significances remain poorly understood. Because deregulated amino acid levels in cancers can affect their biological behavior, we determined the amino acid levels in miR122-silenced mouse liver tissues, in which intracellular arginine levels were significantly increased. The increased intracellular arginine levels were through upregulation of the solute carrier family 7 (SLC7A1), a transporter of arginine and a direct target of miR122. Arginine is the substrate for nitric oxide (NO) synthetase, and intracellular NO levels were increased in miR122-silenced HCC cells, with increased resistance to sorafenib, a multikinase inhibitor. Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib. Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib. These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset.

No MeSH data available.


Related in: MedlinePlus