RESUMO
BACKGROUND: The epithelial malignant tumor known as cholangiocarcinoma (CCA) is most commonly found in Southeast Asia, particularly in northeastern Thailand. Previous research has indicated that the overexpression of acyl-CoA synthetase long-chain family member 4 (ACSL4), solute carrier family 7 member 11 (SLC7A11), and ChaC glutathione-specific γ-glutamylcyclotransferase (CHAC1) as ferroptosis-related proteins is associated with poorer prognosis in several cancers. The role of these three proteins in CCA is still unclear. The present study aimed to investigate the expression levels of ACSL4, SLC7A11, and CHAC1, all potential ferroptosis biomarkers, in CCA. METHODS: The ACSL4, SLC7A11, and CHAC1 protein expression levels in 137 CCA tissues were examined using immunohistochemistry, while 61 CCA serum samples were evaluated using indirect ELISA. The associations between the expression levels of ACSL4, SLC7A11, and CHAC1 and patient clinicopathological data were evaluated to determine the clinical significance of these proteins. RESULTS: The expression levels of ACSL4, SLC7A11, and CHAC1 were assessed in CCA tissues. A significant association was observed between high ACSL4 levels and extrahepatic CCA, tumor growth type, and elevated alanine transferase (ALT). There was also a positive association between elevated SLC7A11 levels and tumor growth type. Additionally, the upregulation of CHAC1 was significantly associated with a shorter survival time in patients. High levels of ACSL4 and SLC7A11 in CCA sera were both significantly associated with advanced tumor stages and abnormal liver function test results, indicating that they could be used as a reliable prognostic biomarker panel in patients with CCA. CONCLUSIONS: The results of the present study demonstrated that the upregulation of ACSL4, SLC7A11, and CHAC1 could be used as a valuable biomarker panel for predicting prognosis parameters in CCA. Furthermore, ACSL4 and SLC7A11 could potentially serve as complementary markers for improving the accuracy of prognosis prediction when CCA sera is used. These less invasive biomarkers could facilitate effective treatment planning.
RESUMO
BACKGROUND/AIM: Serine/threonine kinase 11 (STK11), a tumor suppressor, controls 5' AMP-activated protein kinase (AMPK) signaling in a variety of cellular functions. Mutated STK11 has been identified as a novel driver gene that promotes cancer progression. The purpose of this study was to investigate the alteration of STK11 and its correlation with clinicopathological data in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Gene mutation and expression analyses were performed using cBioportal and Gene Expression Profiling Interactive Analysis version 2 (GEPIA2). qRT-PCR was performed to measure STK11 mRNA levels and immunohistochemistry was performed to investigate STK11 protein expression in CCA tissues. RESULTS: The results from publicly available cancer datasets showed that 2.7% of CCA cases had STK11 mutations. Most of STK11 gene mutations are of the truncating type and result in low STK11 mRNA and protein expression. We detected a correlation between STK11 mutation status and the tendency for shorter patient survival. The results of qRT-PCR revealed that STK11 mRNA levels were statistically significantly lower in CCA patients with mutated STK11 compared to those with wild-type STK11 (p-value=0.013). Immunohistochemical staining showed high STK11 expression in 43.8% and low expression in 56.2% of CCA tissues examined. Low STK11 protein expression resulted in poor prognosis compared with high STK11 expression, especially in CCA papillary carcinoma. Univariate and multivariate analysis revealed that high STK11 expression was associated with a decreased hazard ratio of patient survival rates (HR=0.696, p-value=0.06 and HR=0.666, p-value=0.04, respectively). CONCLUSION: Alteration of STK11 mutational or mRNA/protein status might be used as a potential predictive biomarker for the prognosis of the clinical outcomes in CCA patients.