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YAP Subcellular Localization and Hippo Pathway Transcriptome Analysis in Pediatric Hepatocellular Carcinoma

View Article: PubMed Central - PubMed

ABSTRACT

Pediatric hepatocellular carcinoma (HCC) is a rare tumor which is associated with an extremely high mortality rate due to lack of effective chemotherapy. Recently, the Hippo pathway and its transcriptional co-activator Yes-associated protein (YAP) have been shown to play a role in hepatocyte proliferation and development of HCC in animal models. Therefore, we sought to examine the activity of YAP and the expression of Hippo pathway components in tumor and non-neoplastic liver tissue from 7 pediatric patients with moderately differentiated HCC. None of the patients had underlying cirrhosis or viral hepatitis, which is commonly seen in adults with HCC. This highlights a major difference in the pathogenesis of HCC between children and adults. We found a statistically significant increase in YAP nuclear localization in 100% of tumors. YAP target gene (CCNE1, CTGF, Cyr61) mRNA expression was also increased in the tumors that had the most significant increase in YAP nuclear localization. Based on Ki67 co-localization studies YAP nuclear localization was not simply a marker of proliferation. Our results demonstrate a clear increase in YAP activity in moderately differentiated pediatric HCC, providing evidence that it may play an important role in tumor survival and propagation.

No MeSH data available.


YAP localization and gene expression based on fibrolamellar histology.The median level of YAP nuclear localization increased from 5.4% to 14.6% in FLM-HCC (a) and from 8.1% to 25.8% in non-FLM-HCC (b). Non-FLM-HCC also had a greater upregulation of YAP target genes CCNE1 (c,g), CTGF (d,h), Cyr61 (e,i), and c-myc (f,j).
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f9: YAP localization and gene expression based on fibrolamellar histology.The median level of YAP nuclear localization increased from 5.4% to 14.6% in FLM-HCC (a) and from 8.1% to 25.8% in non-FLM-HCC (b). Non-FLM-HCC also had a greater upregulation of YAP target genes CCNE1 (c,g), CTGF (d,h), Cyr61 (e,i), and c-myc (f,j).

Mentions: FLM-HCC is a subtype of HCC characterized by fibrous collagen bands on histology, that tends to affect the pediatric and young adult population, without a background of cirrhosis23. It has recently been linked to a deletion on chromosome 19, leading to the chimeric fusion protein DNAJB1-PRKACA, which has been proposed as a driver mechanism, though confirmatory evidence is still being collected41. This fusion event has a reported frequency of 79–100% in FLM-HCC4142. This high concordance between the histologic findings and the potential genetic driver suggests that FLM-HCC may demonstrate a uniform form of tumor compared to non-FLM-HCC. We therefore sub-analyzed the tumors based on fibrolamellar histology. In our cohort, 4/7 tumors (Patients 1, 2, 5, and 6) were FLM-HCC. Overall, non-FLM-HCC tumors had a greater degree of YAP nuclear localization, proliferative index, and upregulation of the YAP target genes CCNE1, CTGF, and Cyr61 compared to FLM-HCC (Fig. 9). Interestingly, FLM-HCC also had a significant downregulation of c-myc, although the mechanistic implications of this may be of interest in future studies. Clinically, FLM-HCC is known to have a slightly better prognosis than non-FLM-HCC. Whether greater YAP nuclear activity in non-FLM-HCC may be a contributing factor remains to be elucidated.


YAP Subcellular Localization and Hippo Pathway Transcriptome Analysis in Pediatric Hepatocellular Carcinoma
YAP localization and gene expression based on fibrolamellar histology.The median level of YAP nuclear localization increased from 5.4% to 14.6% in FLM-HCC (a) and from 8.1% to 25.8% in non-FLM-HCC (b). Non-FLM-HCC also had a greater upregulation of YAP target genes CCNE1 (c,g), CTGF (d,h), Cyr61 (e,i), and c-myc (f,j).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5015017&req=5

f9: YAP localization and gene expression based on fibrolamellar histology.The median level of YAP nuclear localization increased from 5.4% to 14.6% in FLM-HCC (a) and from 8.1% to 25.8% in non-FLM-HCC (b). Non-FLM-HCC also had a greater upregulation of YAP target genes CCNE1 (c,g), CTGF (d,h), Cyr61 (e,i), and c-myc (f,j).
Mentions: FLM-HCC is a subtype of HCC characterized by fibrous collagen bands on histology, that tends to affect the pediatric and young adult population, without a background of cirrhosis23. It has recently been linked to a deletion on chromosome 19, leading to the chimeric fusion protein DNAJB1-PRKACA, which has been proposed as a driver mechanism, though confirmatory evidence is still being collected41. This fusion event has a reported frequency of 79–100% in FLM-HCC4142. This high concordance between the histologic findings and the potential genetic driver suggests that FLM-HCC may demonstrate a uniform form of tumor compared to non-FLM-HCC. We therefore sub-analyzed the tumors based on fibrolamellar histology. In our cohort, 4/7 tumors (Patients 1, 2, 5, and 6) were FLM-HCC. Overall, non-FLM-HCC tumors had a greater degree of YAP nuclear localization, proliferative index, and upregulation of the YAP target genes CCNE1, CTGF, and Cyr61 compared to FLM-HCC (Fig. 9). Interestingly, FLM-HCC also had a significant downregulation of c-myc, although the mechanistic implications of this may be of interest in future studies. Clinically, FLM-HCC is known to have a slightly better prognosis than non-FLM-HCC. Whether greater YAP nuclear activity in non-FLM-HCC may be a contributing factor remains to be elucidated.

View Article: PubMed Central - PubMed

ABSTRACT

Pediatric hepatocellular carcinoma (HCC) is a rare tumor which is associated with an extremely high mortality rate due to lack of effective chemotherapy. Recently, the Hippo pathway and its transcriptional co-activator Yes-associated protein (YAP) have been shown to play a role in hepatocyte proliferation and development of HCC in animal models. Therefore, we sought to examine the activity of YAP and the expression of Hippo pathway components in tumor and non-neoplastic liver tissue from 7 pediatric patients with moderately differentiated HCC. None of the patients had underlying cirrhosis or viral hepatitis, which is commonly seen in adults with HCC. This highlights a major difference in the pathogenesis of HCC between children and adults. We found a statistically significant increase in YAP nuclear localization in 100% of tumors. YAP target gene (CCNE1, CTGF, Cyr61) mRNA expression was also increased in the tumors that had the most significant increase in YAP nuclear localization. Based on Ki67 co-localization studies YAP nuclear localization was not simply a marker of proliferation. Our results demonstrate a clear increase in YAP activity in moderately differentiated pediatric HCC, providing evidence that it may play an important role in tumor survival and propagation.

No MeSH data available.