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

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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.

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Related in: MedlinePlus

Ki67 expression in moderately differentiated pediatric HCC compared to non-neoplastic liver.Representative examples of tumor and matched non-neoplastic liver are shown at 40x (panels a–e). (Panel f) represents the percentage of Ki67 positive cells in both tumor and non-neoplastic tissue for each patient. Ki67 was increased in all 7 of the tumors.
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f4: Ki67 expression in moderately differentiated pediatric HCC compared to non-neoplastic liver.Representative examples of tumor and matched non-neoplastic liver are shown at 40x (panels a–e). (Panel f) represents the percentage of Ki67 positive cells in both tumor and non-neoplastic tissue for each patient. Ki67 was increased in all 7 of the tumors.

Mentions: In order to assess whether YAP nuclear localization was associated with increased cellular proliferation, the samples were co-stained for Ki67, which is expressed during the active phases of the cell cycle24. There was an increase in the percentage of Ki67-positive cells in all 7 tumor samples (Fig. 4), with an overall fold increase of 5.6 (0.46% to 2.6%). We subsequently examined the co-localization pattern of YAP and Ki67. The number of Ki67-positive tumor cells that also contained nuclear YAP ranged from 5% to 100%, with an overall median of 50% (Fig. 5a). Interestingly, in all tumor samples except for Patient 5, less than 60% of Ki67 positive cells were YAP positive. Patient 5 in fact had a higher percentage of YAP positive cells in both non-neoplastic and tumor cells. The number of YAP-positive tumor cells that also contained nuclear Ki67 ranged from 1.6% to 9.3%, with an overall median of 4.5% (Fig. 5b).


YAP Subcellular Localization and Hippo Pathway Transcriptome Analysis in Pediatric Hepatocellular Carcinoma
Ki67 expression in moderately differentiated pediatric HCC compared to non-neoplastic liver.Representative examples of tumor and matched non-neoplastic liver are shown at 40x (panels a–e). (Panel f) represents the percentage of Ki67 positive cells in both tumor and non-neoplastic tissue for each patient. Ki67 was increased in all 7 of the tumors.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Ki67 expression in moderately differentiated pediatric HCC compared to non-neoplastic liver.Representative examples of tumor and matched non-neoplastic liver are shown at 40x (panels a–e). (Panel f) represents the percentage of Ki67 positive cells in both tumor and non-neoplastic tissue for each patient. Ki67 was increased in all 7 of the tumors.
Mentions: In order to assess whether YAP nuclear localization was associated with increased cellular proliferation, the samples were co-stained for Ki67, which is expressed during the active phases of the cell cycle24. There was an increase in the percentage of Ki67-positive cells in all 7 tumor samples (Fig. 4), with an overall fold increase of 5.6 (0.46% to 2.6%). We subsequently examined the co-localization pattern of YAP and Ki67. The number of Ki67-positive tumor cells that also contained nuclear YAP ranged from 5% to 100%, with an overall median of 50% (Fig. 5a). Interestingly, in all tumor samples except for Patient 5, less than 60% of Ki67 positive cells were YAP positive. Patient 5 in fact had a higher percentage of YAP positive cells in both non-neoplastic and tumor cells. The number of YAP-positive tumor cells that also contained nuclear Ki67 ranged from 1.6% to 9.3%, with an overall median of 4.5% (Fig. 5b).

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