Abstract
Background and Aims Liver cancer comprises of benign or malignant tumors including hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), hepatoblastoma (HB), and other rarer tumor types. There is evidence of aberrant Wnt signaling during initiation and progression of HCC, CC and HB.
Methods We investigated the expression of Wnt/β-catenin transcription related proteins, Cyclin D1, c-Myc, Fra-1 and Pygo-1, in human liver tumors by using an unbiased, quantitative immunohistochemical (qIHC) approach.
Results Semi-automated, unbiased quantitation of individual proteins revealed reduced expression of Cyclin D1 and Pygo-1 in CC (P < 0.0001 and P < 0.01, respectively) and HB (P < 0.05 and P < 0.01, respectively) compared to normal liver (NL). Receiver operating characteristic curves showed Cyclin D1 as a putative marker for CC (AUC > 0.8) that discriminates CC from both NL and HCC (P ≤ 0.0001), and Pygo-1 (AUC > 0.7) as a marker for both CC and HCC (P < 0.01) compared to NL. Combining Cyclin D1/Pygo-1 and applying a logistic regression model further improved the diagnostic potential (classifying 84% of NL and CC cases, P < 0.0001). Quantitative co-localisation of tissue samples simultaneously labeled with the four biomarkers, indicated that co-localisation of both Pygo-1/Fra-1 and c-Myc/Fra-1 was also significantly changed in CC and HCC (P < 0.0001) vs NL. Additionally, co-localisation of Pygo-1/Fra-1, in particular, could also distinguish CC from HCC (P < 0.05).
Conclusion Our results indicate that measurement of Wnt signaling markers could be used to stratify liver cancer.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
bushra.kanwal{at}kcl.ac.uk, yoh.zen{at}nhs.net, maesha.deheragoda{at}nhs.net, Mike.Millar{at}ed.ac.uk, c.thrasivoulou{at}ucl.ac.uk, tamir.rashid{at}kcl.ac.uk, aamir.ahmed{at}kcl.ac.uk
List of Abbreviations HCC, hepatocellular carcinoma; CC, cholangiocarcinoma; HB, hepatoblastoma; qIHC, quantitative immunohistochemistry; NL, normal liver; PLC, primary liver cancer; SLC, secondary liver cancer; iCC, intrahepatic cholangiocarcinoma; eCC, extrahepatic cholangiocarcinoma; pCC, perihilar cholangiocarcinoma; dCC, distal cholangiocarcinoma; HCC-CC, hepatocellular cholangiocarcinoma; FNH, focal nodular hyperplasia; HCA, hepatic adenoma; PAC-LM, pancreatic adenocarcinoma liver metastasis; CRC-LM, colorectal carcinoma liver metastasis; HuLiv-TA, human liver tissue array; pHCC, poorly differentiated hepatocellular carcinoma; wHCC, well-differentiated hepatocellular carcinoma.
Financial support, This study was funded by the Punjab Educational Endowment Fund, Lahore, Pakistan via Chief Minister Merit Scholarship (CMMS-2016) awarded to BK.