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A biochemical comparison of normal human liver and hepatocellular carcinoma ferritins.

ABSTRACT: 1. The iron contents, gel migration rates and isoelectric-focusing patterns of normal liver and hepatocellular carcinoma ferritins from the same patients were compared. 2. Sucrose-density-gradient centrifugation showed that the number of iron atoms per ferritin molecule was decreased to approximately half in carcinoma tissue when compared with normal liver. 3. On electrophoresis, hepatocellular carcinoma ferritin migrates faster and is therefore more negatively charged than normal liver ferritin, thus refuting the general view that the more negatively charged a ferritin molecule the greater its iron content. 4. Comparison of tumour and normal liver ferritin subunit compositions on acid/urea/polyacrylamide gels showed hepatocellular carcinoma ferritin to contain an additional, more negatively charged, subunit to normal liver ferritin. 5. Isoelectric focusing showed that hepatocellular carcinoma tissue contains isoferritins with isoelectric points intermediate between the ranges of normal liver and normal heart isoferritins.

SUBMITTER: Bullock S

PROVIDER: S-EPMC1161441 | biostudies-other | 1980 Mar

REPOSITORIES: biostudies-other

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Project description:The physiological role of autophagy in the progression of liver diseases is still debated. To understand the clinical relevance of autophagy in primary e secondary hepatic tumors, we analyzed the expression of mTOR (mammalian target of rapamycin), a key regulator of autophagy; Raptor (regulatory-associated protein of mTOR); ULK1 (Unc-51 like kinase 1) determinant in the autophagy initiation; LC3 (microtubule-associated protein 1A/1B-light chain 3), a specific marker of autophagosomes; and p62, a selective autophagy receptor. Samples from subjects with chronic hepatitis (n.58), cirrhosis (n.12), hepatocellular carcinoma (HCC, n.56), metastases (n.48) from colorectal cancer and hyperplasia or gallbladder stones (n.7), the latter considered as controls, were examined. Gene expression analysis was carried out in n.213 tissues by absolute q-PCR, while protein expression by Western Blot in n.191 lysates, including tumoral, surrounding tumoral and normal tissues. Nonparametric statistical tests were used for comparing expression levels in the above-mentioned groups. Subgroup analysis was performed considering viral infection and chemotherapy treatment. The mTOR transcriptional level was significantly lower in metastases compared to HCC (P = 0.0001). p-mTOR(Ser2448) and LC3II/LC3I protein levels were significantly higher in metastases compared to HCC (P = 0.008 and P<0.0001, respectively). ULK(Ser757) levels were significantly higher in HCC compared to metastases (P = 0.0002) while the HCV- and HBV- related HCC showed the highest p62 levels. Chemotherapy induced a down-regulation of the p-mTOR(Ser2448) in metastases and in non-tumor surrounding tissues in treated patients compared to untreated (P = 0.001 and P = 0.005, respectively). Conclusions: the different expression of proteins considered, owning their interaction and diverse tissue microenvironment, indicate an impairment of the autophagy flux in primary liver tumors that is critical for the promotion of tumorigenesis process and a coexistence of autophagy inhibition and activation mechanisms in secondary liver tumors. Differences in mTOR and LC3 transcripts emerged in tumor-free tissues, therefore particular attention should be considered in selecting the control group.

Project description:INTRODUCTION:serum alpha-fetoprotein (AFP) was routinely employed as a tumor marker for screening, diagnosis, and treatment follow-up of hepatocellular carcinoma (HCC). However, a substantial proportion of HCC patients had normal AFP level even at an advanced disease status. Few studies to date had tried to explore the nature and behavior of this normal AFP HCC (N-HCC). The purpose of this study was to investigate the clinicopathological characteristics and survival outcome of N-HCC after operation. In addition, potential tumor markers for N-HCC were also sought in an attempt to augment diagnostic ability. METHODS:between 2005 and 2015, patients with hepatocellular carcinoma who were treated with hepatectomy in Chang Gung Memorial Hospital Linkou branch were divided into two groups according to their preoperative serum AFP level (<15 ng/mL: NHCC; ?15 ng/mL: abnormal AFP HCC (A-HCC)). Patient demographic data and clinicopathological variables were collected. Kaplan-Meier and Cox regression multivariate analyses were performed to identify significant risk factors for disease-free survival (DFS) and overall survival (OS) for N-HCC. ELISA and immunohistochemical (IHC) studies were employed to determine the diagnostic accuracy of various tumor markers. RESULTS:a total of 1616 patients (78% male) who underwent liver resection for HCC were included in this study. Of them, 761 patients (47.1%) were N-HCC. N-HCC patients were significantly older with more comorbidities and less hepatitis virus infections. Furthermore, N-HCC had fewer early recurrences (49.6% vs. 60.8%, p < 0.001) and better DFS (44.6 months vs. 23.6 months, p < 0.001) and OS (94.5 months vs. 81.7 months, p < 0.001). Both ELISA and IHC studies demonstrated that glypican-3 (GPC3) would be a promising diagnostic tumor marker for N-HCC. CONCLUSION:N-HCC patients were significantly older and had less hepatitis virus infections or cirrhosis. Their tumors tended to be smaller, less vascular invaded, and well-differentiated. The carcinogenesis of N-HCC may thus not be identical to that of typical HCC. GPC3 would be a promising tumor marker for diagnosing N-HCC. Further study is warranted to validate our findings.

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A biochemical comparison of normal human liver and hepatocellular carcinoma ferritins.

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