Deleted in Liver Cancer 2 (DLC2) protein expression in hepatocellular carcinoma

Deleted in Liver Cancer (DLC) proteins belong to the family of RhoGAPs and are believed to operate as negative regulators of the Rho family of small GTPases. So far, the role of the first identified member from the DLC family, DLC1, was established as a tumor suppressor in hepatocellular carcinoma. The function of its close family relative, DLC2 is unequivocal. In the present study we attempted to determine whether the loss of DLC2 is a common feature of hepatocellular carcinoma tissue. We examined two types of hepatocellular carcinoma- typical and fibrolamellar one. Our analysis revealed that DLC2 protein is not diminished in cancer tissue when compared to non-cancerous liver specimens. What is more, we observed DLC2 to be more abundantly expressed in cancer tissue, particularly in tumors with the inflammation background. In addition, we found that DLC2 gene status was diploid in virtually all tumor samples examined. Our results indicate that DLC2 is not diminished in hepatocellular carcinoma cells. It appears that members of the DLC family, although structurally highly related, may function differently in cancer cells

Loss of the Orphan Nuclear Receptor SHP Is More Pronounced in Fibrolamellar Carcinoma than in Typical Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a major problem in oncology. The molecular mechanisms which underlie its pathogenesis are poorly understood. Recently the Small Heterodimer Partner (SHP), an orphan nuclear receptor, was suggested to be involved as a tumor suppressor in hepatocellular carcinoma development. To date, there are no such studies regarding fibrolamellar carcinoma, a less common variant of HCC, which usually affects young people and displays distinct morphological features. The aim of our project was to evaluate the SHP levels in typical and fibrolamellar hepatocellular carcinoma with respect to the levels of one of the cell cycle regulators, cyclin D1. We assessed the immunoreactivity levels of SHP and cyclin D1 in 48 typical hepatocellular carcinomas, 9 tumors representing the fibrolamellar variant, 29 non malignant liver tissues and 7 macroregenerative nodules. We detected significantly lower SHP immunoreactivity in hepatocellular carcinoma when compared to non malignant liver tissue. Moreover, we found that SHP immunoreactivity is reduced in fibrolamellar carcinoma when compared to typical hepatocellular carcinoma. We also found that SHP is more commonly lost in HCC which arises in the liver with steatosis. The comparison between the cyclin D1 and SHP expression revealed the negative correlation between these proteins in the high grade HCC. Our results indicate that the impact of loss of SHP protein may be even more pronounced in fibrolamellar carcinoma than in a typical form of HCC. Further investigation of mechanisms through which the loss of SHP function may influence HCC formation may provide important information in order to design more effective HCC therapy

Resection of liver metastases from differentiated thyroid cancer: who might benefit? A report of 2 cases with review of literature

Background: Liver metastases of differentiated thyroid cancers (DTC) are uncommon. Surgery has proven to be effective in patients with 131I-negative hepatic lesions. Here, we present two patients who underwent liver resection for metastatic DTC. Case presentation: The first patient is a 36-year-old woman who reported with 70-mm hepatic metastases of papillary thyroid cancer. After primary treatment of cancer, she was disease-free for 8 years when the elevation of TSH levels resulted for the need to search for metastasis. Notably, the 131I SPECT did not show any lesions. The CT scan revealed an 80mm diameter mass in the liver. Histology confirmed metastasis of thyroid cancer. Lack of iodine uptake and the size of lesion excluded treatment with radioactive iodine. Radical resection of the metastasis was performed with good short- and long-term postoperative result. The second patient is a 65-year-old man previously treated for follicular thyroid cancer. When a iodine-negative 70mm diameter metastasis was detected within the liver, he was referred for surgery. Extended right hepatectomy was performed. In a 12-months follow-up, he remained stable, with no signs of recurrence. Conclusions: These two cases show that resection of hepatic metastases of DTC is an option even in the case of large lesions. Given the effectiveness and safety of liver surgery, we reckon that it should be the treatment of choice when possible. The decision to perform surgical treatment should be based on analysis of the ability to perform radical and safe resection

Resekcja wątroby u pacjentów z przerzutami zróżnicowanego raka tarczycy: kto może odnieść korzyści? Opis dwóch przypadków oraz przegląd literatury

Przerzuty zróżnicowanego raka tarczycy do wątroby występują rzadko. W przypadku guzów niewrażliwych na terapię jodem radioaktywnym, jedną z możliwych metod dążenia do poprawy zdrowia pacjenta jest leczenie chirurgiczne. W niniejszym tekście prezentujemy dwa przypadki resekcji wątroby z powodu przerzutów raka brodawkowatego i pęcherzykowego tarczycy. U 36-letniej chorej, pierwotnie leczonej z powodu brodawkowatego raka tarczycy, po ośmiu latach zaobserwowano wzrost TSH. Rutynowo wykonane 131I SPECT nie wykazało patologii. W TK jamy brzusznej uwidoczniono guz w wątrobie. Badanie histologiczne potwierdziło przerzutowy charakter zmiany. W związku z brakiem możliwości leczenia jodem radioaktywnym, kobietę zakwalifikowano do leczenia operacyjnego. Poddano ją radykalnej resekcji wątroby, uzyskując 60-miesięczne przeżycie bez wznowy. Drugi pacjent to 65-letni mężczyzna z pojedynczym przerzutem raka pęcherzykowego tarczycy do wątroby. Brak wrażliwości komórek wykrytego przerzutu na znakowany jod był powodem podjęcia leczenia chirurgicznego. W 12-miesięcznej obserwacji pozostał bez nawrotu choroby. Przedstawione przypadki pokazują, że resekcja przerzutów DTC do wątroby jest dobrym rozwiązaniem nawet w przypadku dużych zmian. Leczenie operacyjne, obok niepozbawionego działań niepożądanych leczenia systemowego, jest skuteczne i bezpieczne. Decyzja o chirurgicznym leczeniu powinna być oparta na analizie możliwości wykonania radykalnej resekcji

Role of damage-specific DNA polymerases in M13 phage mutagenesis induced by a major lipid peroxidation product trans-4-hydroxy-2-nonenal

One of the major lipid peroxidation products trans-4-hydroxy-2-nonenal (HNE), forms cyclic propano- or ethenoadducts bearing six- or seven-carbon atom side chains to G>C>>A>T. To specify the role of SOS DNA polymerases in HNE-induced mutations, we tested survival and mutation spectra in the lacZα gene of M13mp18 phage, whose DNA was treated in vitro with HNE, and which was grown in uvrA- E. coli strains, carrying one, two or all three SOS DNA polymerases. When Pol IV was the only DNA SOS polymerase in the bacterial host, survival of HNE-treated M13 DNA was similar to, but mutation frequency was lower than in the strain containing all SOS DNA polymerases. When only Pol II or Pol V were present in host bacteria, phage survival decreased dramatically. Simultaneously, mutation frequency was substantially increased, but exclusively in the strain carrying only Pol V, suggesting that induction of mutations by HNE is mainly dependent on Pol V. To determine the role of Pol II and Pol IV in HNE induced mutagenesis, Pol II or Pol IV were expressed together with Pol V. This resulted in decrease of mutation frequency, suggesting that both enzymes can compete with Pol V, and bypass HNE-DNA adducts in an error-free manner. However, HNE-DNA adducts were easily bypassed by Pol IV and only infrequently by Pol II. Mutation spectrum established for strains expressing only Pol V, showed that in uvrA- bacteria the frequency of base substitutions and recombination increased in relation to NER proficient strains, particularly mutations at adenine sites. Among base substitutions A:T → C:G, A:T → G:C, G:C → A:T and G:C → T:A prevailed. The results suggest that Pol V can infrequently bypass HNE-DNA adducts inducing mutations at G, C and A sites, while bypass by Pol IV and Pol II is error-free, but for Pol II infrequent

SHP immunoreactivity in normal liver.

<p>A, B – immunohistochemical staining of the normal hepatic lobule; C, D- immunofluorescence staining showing exclusively nuclear (C) or cytoplasmic (D) SHP localization in different lobules; scale bar: A 100 µm; B 20 µm; C,D 25 µm. E- result of the SHP immunohistochemistry preceded with (lower image) or without (upper image) anti-SHP blocking antibody; F- Western blot analysis of three liver (LV1–LV3) lysates, the SHP protein present in a single band; G- Result of the RT-PCR study showing the SHP mRNA in the normal liver; GAPDH mRNA was used as a control.</p

The cyclin D1 expression in hepatocellular carcinoma.

<p>A- the immunoreactivity of cyclin D1 in HCC tumor; B- the cyclin D1 immunoreactivity in fibrolamellar carcinoma; scale bar 5 µm; C- Spearman's rank graph showing a negative correlation between the SHP and cyclin D1 immunoreactivity in G3 hepatocellular carcinoma.</p

SHP immunoreactivity in macroregenerative nodules.

<p>Note uniform staining of all hepatocytes; scale bar A-100 µm, B-50 µm.</p

Clinicopathological characteristic of patients with results of the immunostaining.

<p>Abbreviations: Ca cm maximal tumor size in cm; Inflamm inflammation; G tumor grade; S stage; N normal; C cirrhosis; R HCC recurrence;</p><p>*data not available; n/a not applicable.</p