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Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver.

Li X, Tao J, Cigliano A, Sini M, Calderaro J, Azoulay D, Wang C, Liu Y, Jiang L, Evert K, Demartis MI, Ribback S, Utpatel K, Dombrowski F, Evert M, Calvisi DF, Chen X - Oncotarget (2015)

Bottom Line: Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC).At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways.Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.

ABSTRACT
Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemical patterns of PIK3CA and Yap in human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)Upper panel: stronger immunoreactivity for PIK3CA as well as upregulation of Yap and its increased nuclear accumulation in a HCC (left part of the picture) with a pseudoglandular phenotype when compared to the non-neoplastic surrounding liver (SL; right part of the picture). Lower panel, upregulation of PIK3CA and total and nuclear levels of Yap in a CCA (left part of the figure) when compared with the non-tumorous counterpart (right part of the picture). Abbreviations: CCA, cholangiocarcinoma; HCC, hepatocellular carcinoma; HE, hematoxylin and eosin staining; SL, surrounding liver. Original magnification: 100X.
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Figure 6: Immunohistochemical patterns of PIK3CA and Yap in human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)Upper panel: stronger immunoreactivity for PIK3CA as well as upregulation of Yap and its increased nuclear accumulation in a HCC (left part of the picture) with a pseudoglandular phenotype when compared to the non-neoplastic surrounding liver (SL; right part of the picture). Lower panel, upregulation of PIK3CA and total and nuclear levels of Yap in a CCA (left part of the figure) when compared with the non-tumorous counterpart (right part of the picture). Abbreviations: CCA, cholangiocarcinoma; HCC, hepatocellular carcinoma; HE, hematoxylin and eosin staining; SL, surrounding liver. Original magnification: 100X.

Mentions: Next, we evaluated the possible relationship between PI3K and Yap pathways in human liver cancer. For this purpose, we analyzed a collection of human HCC (n=54), CCA (n=42), and mixed HCC/CCA (n=16) by immunohistochemistry for PIK3CA and Yap staining (Figures 6 and 7). In HCC, upregulation of PIK3CA and nuclear accumulation of Yap were detected in 15 (27.8%) and 38 (70.4%) specimens, respectively. Importantly 9 of 15 (60%) HCC specimens showing upregulation of PIK3CA concomitantly exhibited nuclear localization of the Yap protein (Figure 6). In CCA, PIK3CA levels were induced in 24 of 42 (57.1%) samples, whereas all specimens displayed immunoreactivity for Yap (Figure 6), in accordance with previous reports [22]. Finally, PIK3CA levels were elevated in 11 of 16 (68.8%) mixed HCC/CCA, while Yap nuclear translocation was detected in 14 of the latter specimens (87.8%). Simultaneous upregulation of PIK3CA and nuclear localization of Yap occurred in 10 of 16 (62.5%) mixed HCC/CCA (Figure 7). No association between the staining patterns of PIK3CA and Yap and clinicopathological features of the HCC, CCA, and mixed HCC/CCA patients, including etiology, presence of cirrhosis, α-fetoprotein levels, tumor size, and tumor grading was found (data not shown). Altogether, the present data indicate that induction of PIK3CA and activation of Yap often co-exist in human liver tumors with hepatocellular and cholangiocellular features.


Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver.

Li X, Tao J, Cigliano A, Sini M, Calderaro J, Azoulay D, Wang C, Liu Y, Jiang L, Evert K, Demartis MI, Ribback S, Utpatel K, Dombrowski F, Evert M, Calvisi DF, Chen X - Oncotarget (2015)

Immunohistochemical patterns of PIK3CA and Yap in human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)Upper panel: stronger immunoreactivity for PIK3CA as well as upregulation of Yap and its increased nuclear accumulation in a HCC (left part of the picture) with a pseudoglandular phenotype when compared to the non-neoplastic surrounding liver (SL; right part of the picture). Lower panel, upregulation of PIK3CA and total and nuclear levels of Yap in a CCA (left part of the figure) when compared with the non-tumorous counterpart (right part of the picture). Abbreviations: CCA, cholangiocarcinoma; HCC, hepatocellular carcinoma; HE, hematoxylin and eosin staining; SL, surrounding liver. Original magnification: 100X.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496343&req=5

Figure 6: Immunohistochemical patterns of PIK3CA and Yap in human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)Upper panel: stronger immunoreactivity for PIK3CA as well as upregulation of Yap and its increased nuclear accumulation in a HCC (left part of the picture) with a pseudoglandular phenotype when compared to the non-neoplastic surrounding liver (SL; right part of the picture). Lower panel, upregulation of PIK3CA and total and nuclear levels of Yap in a CCA (left part of the figure) when compared with the non-tumorous counterpart (right part of the picture). Abbreviations: CCA, cholangiocarcinoma; HCC, hepatocellular carcinoma; HE, hematoxylin and eosin staining; SL, surrounding liver. Original magnification: 100X.
Mentions: Next, we evaluated the possible relationship between PI3K and Yap pathways in human liver cancer. For this purpose, we analyzed a collection of human HCC (n=54), CCA (n=42), and mixed HCC/CCA (n=16) by immunohistochemistry for PIK3CA and Yap staining (Figures 6 and 7). In HCC, upregulation of PIK3CA and nuclear accumulation of Yap were detected in 15 (27.8%) and 38 (70.4%) specimens, respectively. Importantly 9 of 15 (60%) HCC specimens showing upregulation of PIK3CA concomitantly exhibited nuclear localization of the Yap protein (Figure 6). In CCA, PIK3CA levels were induced in 24 of 42 (57.1%) samples, whereas all specimens displayed immunoreactivity for Yap (Figure 6), in accordance with previous reports [22]. Finally, PIK3CA levels were elevated in 11 of 16 (68.8%) mixed HCC/CCA, while Yap nuclear translocation was detected in 14 of the latter specimens (87.8%). Simultaneous upregulation of PIK3CA and nuclear localization of Yap occurred in 10 of 16 (62.5%) mixed HCC/CCA (Figure 7). No association between the staining patterns of PIK3CA and Yap and clinicopathological features of the HCC, CCA, and mixed HCC/CCA patients, including etiology, presence of cirrhosis, α-fetoprotein levels, tumor size, and tumor grading was found (data not shown). Altogether, the present data indicate that induction of PIK3CA and activation of Yap often co-exist in human liver tumors with hepatocellular and cholangiocellular features.

Bottom Line: Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC).At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways.Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.

ABSTRACT
Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.

No MeSH data available.


Related in: MedlinePlus