Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs

SummaryHepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. HCC can be cured by radical therapies if early diagnosis is done while the tumor has remained of small size. Unfortunately, diagnosis is commonly late when the tumor has grown and spread. Thus, palliative approaches are usually applied such as transarterial intrahepatic chemoembolization and sorafenib, an anti-angiogenic agent and MAP kinase inhibitor. This latter is the only targeted therapy that has shown significant, although moderate, efficiency in some individuals with advanced HCC. This highlights the need to develop other targeted therapies, and to this goal, to identify more and more pathways as potential targets. The Wnt pathway is a key component of a physiological process involved in embryonic development and tissue homeostasis. Activation of this pathway occurs when a Wnt ligand binds to a Frizzled (FZD) receptor at the cell membrane. Two different Wnt signaling cascades have been identified, called non-canonical and canonical pathways, the latter involving the β-catenin protein. Deregulation of the Wnt pathway is an early event in hepatocarcinogenesis and has been associated with an aggressive HCC phenotype, since it is implicated both in cell survival, proliferation, migration and invasion. Thus, component proteins identified in this pathway are potential candidates of pharmacological intervention. This review focuses on the characteristics and functions of the molecular targets of the Wnt signaling cascade and how they may be manipulated to achieve anti-tumor effects

Expression et activité des isoformes de p63 dans les cellules de carcinome hépatocellulaire

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

p53 functional loss, stemness and hepatocellular carcinoma

The tumor suppressor p53 is a key player in the control of genomic integrity and homeostasis in connection with p63 and p73, the two other members of the p53 family. Loss of functional p53 leads to the proliferation and survival of mature cells and progenitor or stem cells that accumulate genetic alterations, thus favoring tumorigenesis. p53 loss of function, observed in a wide variety of human tumor types, is frequently caused by missense mutations more frequently found in the DNA binding domain, but can also be due to the expression of a plethora of viral and cellular negative regulators. Human hepatocellular carcinoma (HCC) represents a specific situation, first because the TP53 gene mutations pattern exhibits a “hot spot” rarely found in other tumor types that is linked to Aflatoxin B1 exposure and, second, because many HCCs do not exhibit any TP53 mutation. Here, we provide an overview of the current knowledge about the inhibition of p53 functions by the N-terminal (ΔN) truncated forms of the family, and their role in the emergence and maintenance of pre-malignant cells with stem cell characteristics and in HCC development. We focus in particular on the Nanog-IGF1R-ΔNp73 axis that is associated with stem-like features in HCC cells and that may provide an attractive new therapeutic target and help to develop new biomarkers for HCC risk stratification, as well as preventive strategies

p53 genetic abnormalities andmyc activation in human lung carcinoma

International audiencep53 mutations and myc gene amplification and expression were studied in 119 lung carcinomas of all histological types. A mutant p53 immunophenotype was previously found in 47% of these tumors by immunohistochemical analysis. Seven cases exhibited p53 genomic rearrangements on Southern blots. Elevated levels of p53 transcript were found in 12 carcinomas (10%) and decreased levels in 27 carcinomas (23%) on Northern blots. In most of the cases, low levels of transcript were associated with negative immunostaining, whereas elevated levels of mRNA were related to positive immunostaining (mutant immunophenotype). p53 RT/PCR analysis in 10 tumors with absence of transcript on Northern blots revealed only weak or absent expression of normal and/or altered size transcripts. These abnormal transcripts showed deletions, insertions or splicing abnormalities. Taken together, p53 abnormalities were found in 66% of lung carcinomas [52% of neuroendocrine (NE) carcinomas and 75% of NSCLC]. c-myc was found to be activated in 24% (10/42) of these NE and in 48% (33/69) of these NSCLC carcinomas using Southern- and Northern-blot techniques. In addition, L- and N-myc genes were also activated in 26% (10/42) of NE carcinomas. No correlation was found between p53 mutations and myc activation in SCLC or in NSCLC, but their association was significantly more frequent in NSCLC than in SCLC. These results indicate that the p53-positive immunophenotype uncovers the occurrence of p53 point mutations in lung cancer and that p53 and c-myc gene alterations are important but represent independent occurrences in the development of lung tumors

The Tumour Suppressor Gene TP53: Implications for Cancer Management and Therapy.

Abstract not availableJRC.I-Institute for Health and Consumer Protection (Ispra

Clinical significance of high expression of a specific solute carrier transporter in HCC.

303 Background: Hepatocellular carcinoma (HCC) is the third cause of cancer-related death. GNS561 (Genoscience Pharma, France) is a small molecule inducing apoptosis by lysosome inhibition and caspase activation. GNS561 has high hepatotropism and anti-tumorigenic capacity on tumor bulk and cancer stem cells. Its main target is a specific solute carrier transporter (SLCt). We describe here the clinical relevance of the overexpression of SLCt in HCC patients. Methods: The expression of SLCt was investigated by iQRT-PCR in surgically resected HCC tumors (T) and the matched non-tumor (NT) liver tissues (n=180) as well as healthy livers (HL) devoid of chronic or acute disease (n=10). Pearson's chi-squared test was employed for significant correlation tests while univariate and multivariate survival analysis were performed by Cox proportional hazard ratio (HR) method. Results: SLCt was overexpressed in 40.5% of T and 30.3% of NT as compared to HL. High SLCt in T was associated with microvascular emboli (p=0.034) and expression of the cancer stem cell markers Sox2 (p=0.025) and CD133 (p=0.034). High SLCt in NT correlated with cirrhosis (p=0.009) and presence of satellite nodules (p<0.001). Univariate analysis showed association between high SLCt in T and shortened overall survival (OS) (HR=1.08, p=0.020), lower progression-free survival (PFS) (HR=1.76, p=0.006) as well as early recurrence-free survival (ERFS) (within 2 years post-surgery) (HR=1.88, p=0.008). In multivariate analysis, high SLCt tended to be an independent factor for OS, and this was strongly significant for PFS and ERFS. High SLCt in NT, is quite a poor outcome factor on late recurrence-free survival (HR=2.33, p=0.056) together with cirrhosis in univariate analysis, but remained dependent of cirrhosis in multivariate analysis. Late recurrence is linked to the intrinsic tumorigenic status of the liver. Conclusions: Overexpression of the SLCt in HCC tumors is associated to stemness features and appears as a poor outcome factor impacting on early recurrence. Further, SLCt in NT is associated with development of de-novo HCC. Validation cohorts and prospective assessments are needed to define high SLCt as a potential biomarker of HCC stemness and patient outcome