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BACKGROUND/AIM: Our objectives in this study were to (i) evaluate the clinical significance of X-box-binding protein 1 (XBP1) expression in cases of hepatocellular carcinoma (HCC) and (ii) assess the potential of XBP1 to be used as a prognostic biomarker. PATIENTS AND METHODS: The expression of XBP1 protein in 267 HCC tissue specimens was measured using immunohistochemistry in order to characterize the associations among XBP1 expression, clinicopathological factors and survival outcomes. Survival analysis using follow-up data was used to assess the prognostic value of XBP1 in cases of HCC. Immunohistochemistry revealed a significant decrease in cytoplasmic XBP1 protein expression in HCC tumor tissue. RESULTS: Immunoreactivity results showed that low cytoplasmic XBP1 expression was significantly associated with vascular invasion, as well as poor 5-year overall survival and long-term disease-specific (DSS) and disease-free (DFS) survival rates. Kaplan-Meier survival curves further confirmed a significant association between low cytoplasmic XBP1 protein expression and poor DSS and DFS. Univariate and multivariate analyses revealed that XBP1 expression, tumor differentiation, vascular invasion, tumor stage, and the rate of recurrence were linked to DSS, while low cytoplasmic XBP1 expression remained an independent predictor of poor DSS. Our analysis also revealed that XBP1 expression, tumor differentiation, vascular invasion, and T classification were linked to DFS, while low cytoplasmic XBP1 expression remained an independent predictor of poor DFS. CONCLUSION: Low cytoplasmic XBP1 protein expression may play an important role in the pathogenesis of HCC, which suggests that XBP1 could potentially be targeted to benefit therapeutic strategies for HCC.

BACKGROUND/AIM: Our objectives in this study were to (i) evaluate the clinical significance of X-box-binding protein 1 (XBP1) expression in cases of hepatocellular carcinoma (HCC) and (ii) assess the potential of XBP1 to be used as a prognostic biomarker. PATIENTS AND METHODS: The expression of XBP1 protein in 267 HCC tissue specimens was measured using immunohistochemistry in order to characterize the associations among XBP1 expression, clinicopathological factors and survival outcomes. Survival analysis using follow-up data was used to assess the prognostic value of XBP1 in cases of HCC. Immunohistochemistry revealed a significant decrease in cytoplasmic XBP1 protein expression in HCC tumor tissue. RESULTS: Immunoreactivity results showed that low cytoplasmic XBP1 expression was significantly associated with vascular invasion, as well as poor 5-year overall survival and long-term disease-specific (DSS) and disease-free (DFS) survival rates. Kaplan-Meier survival curves further confirmed a significant association between low cytoplasmic XBP1 protein expression and poor DSS and DFS. Univariate and multivariate analyses revealed that XBP1 expression, tumor differentiation, vascular invasion, tumor stage, and the rate of recurrence were linked to DSS, while low cytoplasmic XBP1 expression remained an independent predictor of poor DSS. Our analysis also revealed that XBP1 expression, tumor differentiation, vascular invasion, and T classification were linked to DFS, while low cytoplasmic XBP1 expression remained an independent predictor of poor DFS. CONCLUSION: Low cytoplasmic XBP1 protein expression may play an important role in the pathogenesis of HCC, which suggests that XBP1 could potentially be targeted to benefit therapeutic strategies for HCC.

Specifying the primitive streak (PS) guides stem cell differentiation in vitro; however, much remains to be learned about the transcription networks that direct anterior and posterior PS cells (APS and PPS, respectively) to differentiate to distinct mesendodermal subpopulations. Here, we show that APS genes are predominantly induced in YAP1-/- human embryonic stem cells (hESCs) in response to ACTIVIN. This finding establishes the Hippo effector YAP1 as a master regulator of PS specification, functioning to repress ACTIVIN-regulated APS genes in hESCs. Moreover, transient exposure of wild-type hESCs to dasatinib, a potent C-SRC/YAP1 inhibitor, enables differentiation to APS-derived endoderm and cardiac mesoderm in response to ACTIVIN. Importantly, these cells can differentiate efficiently to normal beating cardiomyocytes without the cytoskeletal defect seen in YAP1-/- hESC-derived cardiomyocytes. Overall, we uncovered an induction mechanism to generate APS cells using a cocktail of ACTIVIN and YAP1i molecules that holds practical implications for hESC and induced pluripotent stem cell differentiation into distinct mesendodermal lineages.

Specifying the primitive streak (PS) guides stem cell differentiation in vitro; however, much remains to be learned about the transcription networks that direct anterior and posterior PS cells (APS and PPS, respectively) to differentiate to distinct mesendodermal subpopulations. Here, we show that APS genes are predominantly induced in YAP1-/- human embryonic stem cells (hESCs) in response to ACTIVIN. This finding establishes the Hippo effector YAP1 as a master regulator of PS specification, functioning to repress ACTIVIN-regulated APS genes in hESCs. Moreover, transient exposure of wild-type hESCs to dasatinib, a potent C-SRC/YAP1 inhibitor, enables differentiation to APS-derived endoderm and cardiac mesoderm in response to ACTIVIN. Importantly, these cells can differentiate efficiently to normal beating cardiomyocytes without the cytoskeletal defect seen in YAP1-/- hESC-derived cardiomyocytes. Overall, we uncovered an induction mechanism to generate APS cells using a cocktail of ACTIVIN and YAP1i molecules that holds practical implications for hESC and induced pluripotent stem cell differentiation into distinct mesendodermal lineages.