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Net expression inhibits the growth of pancreatic ductal adenocarcinoma cell PL45 in vitro and in vivo.

Li B, Wan X, Zhu Q, Li L, Zeng Y, Hu D, Qian Y, Lu L, Wang X, Meng X - PLoS ONE (2013)

Bottom Line: Thus, it is important to better understand its molecular mechanisms and to develop more effective treatments for the disease.The ternary complex factor Net, which exerts its strong inhibitory function on transcription of proto-oncogene gene c-fos by forming ternary complexes with a second transcription factor, has been suspected of being involved in pancreatic cancer and other tumors biology.Furthermore, using in vitro and in vivo model systems, we found that overexpression of Net inhibited cell growth and survival and induced cell apoptosis in human pancreatic ductal adenocarcinoma cell PL45; the mechanisms by which Net inhibited the cell cycle progression were mainly through P21-Cyclin D1/CDK4 Pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

ABSTRACT
Pancreatic ductal adenocarcinoma has a poor prognosis due to late diagnosis and a lack of effective therapeutic options. Thus, it is important to better understand its molecular mechanisms and to develop more effective treatments for the disease. The ternary complex factor Net, which exerts its strong inhibitory function on transcription of proto-oncogene gene c-fos by forming ternary complexes with a second transcription factor, has been suspected of being involved in pancreatic cancer and other tumors biology. In this study, we found that the majority of pancreatic ductal adenocarcinoma tissues and cell lines had weak or no expression of Net, whereas significantly high level of Net expression occurred in paired adjacent normal tissues we studied. Furthermore, using in vitro and in vivo model systems, we found that overexpression of Net inhibited cell growth and survival and induced cell apoptosis in human pancreatic ductal adenocarcinoma cell PL45; the mechanisms by which Net inhibited the cell cycle progression were mainly through P21-Cyclin D1/CDK4 Pathway. Our data thus suggested that Net might play an important role in pancreatic carcinogenesis, possibly by acting as a tumor suppressor gene.

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The possible regulatory model of effect of Net on pancreatic ductal adenocarcinoma.Net inhibits the growth of pancreatic ductal adenocarcinoma cell by inhibiting the expression of c-fos, subsequently inactivating the transcription activity of AP-1, followed by activation of p21 to antagonize the effects of Cyclin D/CDK4 on cell cycle progression, and ultimately leading to cell death. On the contrary, phosphorylation of Net is activated by intra or extracellular stimulation signals through Ras-MAPKs pathway, which results in downregulation of Net expression and lack of inhibitory ability on c-fos transcription, thus promoting cell proliferation.
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pone-0057818-g005: The possible regulatory model of effect of Net on pancreatic ductal adenocarcinoma.Net inhibits the growth of pancreatic ductal adenocarcinoma cell by inhibiting the expression of c-fos, subsequently inactivating the transcription activity of AP-1, followed by activation of p21 to antagonize the effects of Cyclin D/CDK4 on cell cycle progression, and ultimately leading to cell death. On the contrary, phosphorylation of Net is activated by intra or extracellular stimulation signals through Ras-MAPKs pathway, which results in downregulation of Net expression and lack of inhibitory ability on c-fos transcription, thus promoting cell proliferation.

Mentions: In summary, the present results suggested that Net has the potential to inhibit the growth of human pancreatic ductal adenocarcinoma cell PL45 and induce cellular apoptosis in vitro and in vivo. The inhibitory mechanism is presumably by inhibiting the expression of c-fos, subsequently inactivating the transcription activity of AP-1, followed by activating of p21 to antagonize the effects of Cyclin D/CDK4 on cell cycle progression, and ultimately leading to cell death. On the contrary, intra or extracellular signals through Ras-MAPKs pathway induce phosphorylation of Net, which results in downregulating Net expression and disabling inhibitory ability of Net on c-fos transcription, thus accelerating cell cycle progression and promoting cell proliferation (the possible regulatory model as showed in Fig. 5). Further studies will be pursued to fully characterized the mechanism.


Net expression inhibits the growth of pancreatic ductal adenocarcinoma cell PL45 in vitro and in vivo.

Li B, Wan X, Zhu Q, Li L, Zeng Y, Hu D, Qian Y, Lu L, Wang X, Meng X - PLoS ONE (2013)

The possible regulatory model of effect of Net on pancreatic ductal adenocarcinoma.Net inhibits the growth of pancreatic ductal adenocarcinoma cell by inhibiting the expression of c-fos, subsequently inactivating the transcription activity of AP-1, followed by activation of p21 to antagonize the effects of Cyclin D/CDK4 on cell cycle progression, and ultimately leading to cell death. On the contrary, phosphorylation of Net is activated by intra or extracellular stimulation signals through Ras-MAPKs pathway, which results in downregulation of Net expression and lack of inhibitory ability on c-fos transcription, thus promoting cell proliferation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585156&req=5

pone-0057818-g005: The possible regulatory model of effect of Net on pancreatic ductal adenocarcinoma.Net inhibits the growth of pancreatic ductal adenocarcinoma cell by inhibiting the expression of c-fos, subsequently inactivating the transcription activity of AP-1, followed by activation of p21 to antagonize the effects of Cyclin D/CDK4 on cell cycle progression, and ultimately leading to cell death. On the contrary, phosphorylation of Net is activated by intra or extracellular stimulation signals through Ras-MAPKs pathway, which results in downregulation of Net expression and lack of inhibitory ability on c-fos transcription, thus promoting cell proliferation.
Mentions: In summary, the present results suggested that Net has the potential to inhibit the growth of human pancreatic ductal adenocarcinoma cell PL45 and induce cellular apoptosis in vitro and in vivo. The inhibitory mechanism is presumably by inhibiting the expression of c-fos, subsequently inactivating the transcription activity of AP-1, followed by activating of p21 to antagonize the effects of Cyclin D/CDK4 on cell cycle progression, and ultimately leading to cell death. On the contrary, intra or extracellular signals through Ras-MAPKs pathway induce phosphorylation of Net, which results in downregulating Net expression and disabling inhibitory ability of Net on c-fos transcription, thus accelerating cell cycle progression and promoting cell proliferation (the possible regulatory model as showed in Fig. 5). Further studies will be pursued to fully characterized the mechanism.

Bottom Line: Thus, it is important to better understand its molecular mechanisms and to develop more effective treatments for the disease.The ternary complex factor Net, which exerts its strong inhibitory function on transcription of proto-oncogene gene c-fos by forming ternary complexes with a second transcription factor, has been suspected of being involved in pancreatic cancer and other tumors biology.Furthermore, using in vitro and in vivo model systems, we found that overexpression of Net inhibited cell growth and survival and induced cell apoptosis in human pancreatic ductal adenocarcinoma cell PL45; the mechanisms by which Net inhibited the cell cycle progression were mainly through P21-Cyclin D1/CDK4 Pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

ABSTRACT
Pancreatic ductal adenocarcinoma has a poor prognosis due to late diagnosis and a lack of effective therapeutic options. Thus, it is important to better understand its molecular mechanisms and to develop more effective treatments for the disease. The ternary complex factor Net, which exerts its strong inhibitory function on transcription of proto-oncogene gene c-fos by forming ternary complexes with a second transcription factor, has been suspected of being involved in pancreatic cancer and other tumors biology. In this study, we found that the majority of pancreatic ductal adenocarcinoma tissues and cell lines had weak or no expression of Net, whereas significantly high level of Net expression occurred in paired adjacent normal tissues we studied. Furthermore, using in vitro and in vivo model systems, we found that overexpression of Net inhibited cell growth and survival and induced cell apoptosis in human pancreatic ductal adenocarcinoma cell PL45; the mechanisms by which Net inhibited the cell cycle progression were mainly through P21-Cyclin D1/CDK4 Pathway. Our data thus suggested that Net might play an important role in pancreatic carcinogenesis, possibly by acting as a tumor suppressor gene.

Show MeSH
Related in: MedlinePlus