Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1- tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells

Lokale therapie des rektum karzinoms. Verfohren in kurative intention

In selected patients, local excision of rectal cancer may be an alternative to radical surgery such as abdominoperineal excision of the rectum or anterior resection. Local excision carries lower mortality and morbidity without the functional disturbance. Patients selection is the most important factor in successful local excision. It should be restricted to patients with T1-T2,N0 stage without high risk factors

Low rectal cancer--what is the choice?

In patients operated on for low rectal cancer, the functional results, disease recurrence, and survival have been evaluated with respect to the type of surgery performed. Particular attention was paid to analysis of the pathologic aspects, considered in our opinion, as risk factors for recurrence. The investigation was carried out on 131 patients, of whom 70 received anterior resection, 55 abdominoperineal resection, and 6 local treatment. Abdominoperineal resection was carried out in more advanced disease. Postoperative mortality was 2.1 percent after anterior resection and 0 after abdominoperineal resection or local treatment. Follow-up, carried out in 96 patients (44 anterior resections, 46 abdominoperineal resections, and 6 local treatments), ranged from 12 to 84 (mean, 33.3) months. Recurrence rate was 53.3 percent after abdominoperineal resection and 28.9 percent after anterior resection. Recurrence appears not be related to the treatment performed, but rather depend on certain aspects of the neoplasm such as diameter exceeding 5 cm, extraparietal infiltration, lymphangitis, and tumor indifferentiation. We observed anastomotic recurrence in 28.6 percent of patients with a margin of less than 2 cm. An intensive follow-up scheme enabled us to recognize this type of recurrence early and to reoperate with radical intent. One year after anterior resection functional results were encouraging. No severe incontinence was reported. Local treatment was performed in carefully selected patients (T1, N0) and no cases of mortality or recurrence were observed

Lymphnode dissection in papillary or follicular thyroid carcinoma.

Abstract BACKGROUND: Prospective randomized studies aimed at evaluating the different therapeutic protocols for the treatment of papillary or follicular carcinoma are lacking at the moment. Although total thyroidectomy is widely accepted, indication to locoregional lymphadenectomy is strongly debated. MATERIALS AND METHODS: Fifty-four patients with papillary or follicular thyroid carcinoma (45 papillary and 9 follicular) underwent functional evaluation of the gland before intervention, FNAB included Surgical management was carried out as follows: 41 total thyroidectomy, 6 lobectomy with further totalization in 5, 6 total thyroidectomy plus central compartment lymphadenectomy and 1 left laterocervical lymphadenectomy (papillary carcinoma, treated elsewhere through total thyroidectomy plus central and right laterocervical lymphadenectomy). All operated patients were submitted to whole body scintigraphy and treated thereafter by radiometabolic therapy and chronic hormone suppressive therapy. RESULTS: Fifty-one patients are currently alive, 3 died from non-related causes; surgical complications included 1 permanent impairment of inferior laryngeal nerve function and 1 case of hypoparathyroidism. The follow-up was from 1 to 139 months. DISCUSSION: The optimal treatment of lymph node metastases, especially for papillary carcinomas, has not yet been defined. Two trends are evident concerning lymphadenectomy: the first one suggests routine lymphadenectomy, the second supports lymphadenectomy by necessity. In follicular carcinoma lymphadenectomy is recommended only in the presence of clinical evidence of lymph node involvement. Occult differentiated carcinoma does not require any further treatment of lymph nodes. CONCLUSION: Considering the high efficacy of radiometabolic treatment after total thyroidectomy combined with chronic TSH inhibition through L-tyrosine administration, lymphadenectomy is suggested only by necessity

Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value

Background: The DNA-repair gene DNA-dependent kinase catalytic subunit (DNA-PKcs) favours or inhibits carcinogenesis, depending on the cancer type. Its role in human hepatocellular carcinoma (HCC) is unknown. Methods: DNA-dependent protein kinase catalytic subuni, H2A histone family member X (H2AFX) and heat shock transcription factor-1 (HSF1) levels were assessed by immunohistochemistry and/or immunoblotting and qRT-PCR in a collection of human HCC. Rates of proliferation, apoptosis, microvessel density and genomic instability were also determined. Heat shock factor-1 cDNA or DNA-PKcs-specific siRNA were used to explore the role of both genes in HCC. Activator protein 1 (AP-1) binding to DNA-PKcs promoter was evaluated by chromatin immunoprecipitation. Kaplan-Meier curves and multivariate Cox model were used to study the impact on clinical outcome. Results: Total and phosphorylated DNA-PKcs and H2AFX were upregulated in HCC. Activated DNA-PKcs positively correlated with HCC proliferation, genomic instability and microvessel density, and negatively with apoptosis and patient's survival. Proliferation decline and massive apoptosis followed DNA-PKcs silencing in HCC cell lines. Total and phosphorylated HSF1 protein, mRNA and activity were upregulated in HCC. Mechanistically, we demonstrated that HSF1 induces DNA-PKcs upregulation through the activation of the MAPK/JNK/AP-1 axis. Conclusion: DNA-dependent protein kinase catalytic subunit transduces HSF1 effects in HCC cells, and might represent a novel target and prognostic factor in human HCC.BACKGROUND: The DNA-repair gene DNA-dependent kinase catalytic subunit (DNA-PKcs) favours or inhibits carcinogenesis, depending on the cancer type. Its role in human hepatocellular carcinoma (HCC) is unknown. METHODS: DNA-dependent protein kinase catalytic subunit, H2A histone family member X (H2AFX) and heat shock transcription factor-1 (HSF1) levels were assessed by immunohistochemistry and/or immunoblotting and qRT-PCR in a collection of human HCC. Rates of proliferation, apoptosis, microvessel density and genomic instability were also determined. Heat shock factor-1 cDNA or DNA-PKcs-specific siRNA were used to explore the role of both genes in HCC. Activator protein 1 (AP-1) binding to DNA-PKcs promoter was evaluated by chromatin immunoprecipitation. Kaplan-Meier curves and multivariate Cox model were used to study the impact on clinical outcome. RESULTS: Total and phosphorylated DNA-PKcs and H2AFX were upregulated in HCC. Activated DNA-PKcs positively correlated with HCC prolifer