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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.


Related in: MedlinePlus

YAP nuclear localization is increased in moderately differentiated pediatric HCC compared to non-neoplastic liver.Representative sections from tumor and matched non-neoplastic liver are shown at 40x (panels a–e, g–k, m–q, s–w, y–ac, ae–ai, ak–ao). The quantitative analysis of YAP nuclear staining for each sample is shown in panels f, l, r, x, ad, aj, and ap. YAP expression in the nuclei of tumor cells is increased for all patients. *p = 0.01; **p = 0.05.
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f1: YAP nuclear localization is increased in moderately differentiated pediatric HCC compared to non-neoplastic liver.Representative sections from tumor and matched non-neoplastic liver are shown at 40x (panels a–e, g–k, m–q, s–w, y–ac, ae–ai, ak–ao). The quantitative analysis of YAP nuclear staining for each sample is shown in panels f, l, r, x, ad, aj, and ap. YAP expression in the nuclei of tumor cells is increased for all patients. *p = 0.01; **p = 0.05.

Mentions: YAP is transcriptionally active when it is localized to the nucleus11. Therefore, we sought to determine whether YAP nuclear localization was different between tumor and non-neoplastic liver cells. All examined tumors were classified as moderately differentiated HCC by one expert liver pathologist (APA) (Table 1). YAP nuclear localization was significantly increased in 7/7 HCC tumor samples (Fig. 1). YAP subcellular localization was further subdivided into the following patterns: nuclear only, cytoplasmic only, both nuclear and cytoplasmic, or no staining (Fig. 2)13. Of note, all 7 tumors demonstrated both nuclear and cytoplasmic YAP. Specifically, the cytoplasmic staining seen in the tumor tissue localized immediately adjacent to the nuclei, which was a distinct pattern not seen in non-neoplastic liver. Overall, a median of 7.33% (range 0.0% to 25.47%) of non-neoplastic cells demonstrated nuclear YAP, as compared to 14.39% (range 4.6–51.7%) in the tumor samples, resulting in a significant median fold increase of 1.96 (Fig. 3).


YAP Subcellular Localization and Hippo Pathway Transcriptome Analysis in Pediatric Hepatocellular Carcinoma
YAP nuclear localization is increased in moderately differentiated pediatric HCC compared to non-neoplastic liver.Representative sections from tumor and matched non-neoplastic liver are shown at 40x (panels a–e, g–k, m–q, s–w, y–ac, ae–ai, ak–ao). The quantitative analysis of YAP nuclear staining for each sample is shown in panels f, l, r, x, ad, aj, and ap. YAP expression in the nuclei of tumor cells is increased for all patients. *p = 0.01; **p = 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015017&req=5

f1: YAP nuclear localization is increased in moderately differentiated pediatric HCC compared to non-neoplastic liver.Representative sections from tumor and matched non-neoplastic liver are shown at 40x (panels a–e, g–k, m–q, s–w, y–ac, ae–ai, ak–ao). The quantitative analysis of YAP nuclear staining for each sample is shown in panels f, l, r, x, ad, aj, and ap. YAP expression in the nuclei of tumor cells is increased for all patients. *p = 0.01; **p = 0.05.
Mentions: YAP is transcriptionally active when it is localized to the nucleus11. Therefore, we sought to determine whether YAP nuclear localization was different between tumor and non-neoplastic liver cells. All examined tumors were classified as moderately differentiated HCC by one expert liver pathologist (APA) (Table 1). YAP nuclear localization was significantly increased in 7/7 HCC tumor samples (Fig. 1). YAP subcellular localization was further subdivided into the following patterns: nuclear only, cytoplasmic only, both nuclear and cytoplasmic, or no staining (Fig. 2)13. Of note, all 7 tumors demonstrated both nuclear and cytoplasmic YAP. Specifically, the cytoplasmic staining seen in the tumor tissue localized immediately adjacent to the nuclei, which was a distinct pattern not seen in non-neoplastic liver. Overall, a median of 7.33% (range 0.0% to 25.47%) of non-neoplastic cells demonstrated nuclear YAP, as compared to 14.39% (range 4.6–51.7%) in the tumor samples, resulting in a significant median fold increase of 1.96 (Fig. 3).

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.


Related in: MedlinePlus