The Adaptability of Chromosomal Instability in Cancer Therapy and Resistance.

Variation in chromosome structure is a central source of DNA damage and DNA damage response, together representinga major hallmark of chromosomal instability. Cancer cells under selective pressure of therapy use DNA damage and DNA damage response to produce newfunctional assets as an evolutionary mechanism. Recent efforts to understand DNA damage/chromosomal instability and elucidate its role in initiation or progression of cancer have also disclosed its vulnerabilities represented by inappropriate DNA damage response, chromatin changes, andinflammation.

The pattern of gene copy number alteration (CNAs) in hepatocellular carcinoma: an in silico analysis.

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer that occurs predominantly in patients with previous liver conditions. In the absence of an ideal screening modality, HCC is usually diagnosed at an advanced stage. Recent studies show that loss or gain of genomic materials can activate the oncogenes or inactivate the tumor suppressor genes to predispose cells toward carcinogenesis.

DNA Damage Response Protein CHK2 Regulates Metabolism in Liver Cancer.

Defective mitosis with chromosome missegregation can have a dramatic effect on genome integrity by causing DNA damage, activation of the DNA damage response (DDR), and chromosomal instability. Although this is an energy-dependent process, mechanisms linking DDR to cellular metabolism are unknown. Here we show that checkpoint kinase 2 (CHK2), a central effector of DDR, regulates cellular energy production by affecting glycolysis and mitochondrial functions.

Defective mitosis-linked DNA damage response and chromosomal instability in liver cancer.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, represents a health problem in hepatic viruses-eradicating era because obesity, type 2 diabetes, and nonalcoholic steatohepatitis (NASH) are considered emerging pathogenic factors. Metabolic disorders underpin mitotic errors that lead to numerical and structural chromosome aberrations in a significant proportion of cell divisions. Here, we review that genomically unstable HCCs show evidence for a paradoxically DNA damage response (DDR) which leads to ongoing chromosome segregation errors.

New molecular targets for functionalized nanosized drug delivery systems in personalized therapy for hepatocellular carcinoma.

Hepatocellular carcinoma, the most frequent solid tumor of the liver, has a very poor prognosis, being the second most common cause of death from cancer worldwide. The incidence and mortality of this liver tumor are increasing in most areas of the world as a consequence of aging and the emerging of new risk factors such as the metabolic syndrome, beside the recognized role of hepatitis B and C viral infections and alcohol abuse. Despite the increasing knowledge on the molecular mechanisms underlying hepatic carcinogenesis, effective therapeutic strategies are still an unmet clinical need.

CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression.

Objective: Chromosomal instability (CIN) is the most common form of genomic instability, which promotes hepatocellular carcinoma (HCC) progression by enhancing tumour heterogeneity, drug resistance and immunity escape. CIN per se is an important factor of DNA damage, sustaining structural chromosome abnormalities but the underlying mechanisms are unknown.

Design: DNA damage response protein checkpoint kinase 2 (Chk2) expression was evaluated in an animal model of diethylnitrosamine-induced HCC characterised by DNA damage and elevated mitotic errors.

Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy.

Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. Different etiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation. Continuous cycles of this destructive-regenerative process culminates in liver cirrhosis which is characterized by regenerating nodules that progress to dysplastic nodules and ultimately HCC.

Determination and Characterization of Tetraspanin-Associated Phosphoinositide-4 Kinases in Primary and Neoplastic Liver Cells.

Accumulating evidence implicates phosphoinositide 4-phosphate as a regulatory molecule in its own right recruiting specific effector proteins to cellular membranes. Here, we describe biochemical and immunocytochemical methods to evaluate tetraspanin-associated phosphoinositide-4 kinases activity in primary human hepatic stellate cells (hHSC) and neoplastic hepatoblastoma cells.

CD63 tetraspanin is a negative driver of epithelial-to-mesenchymal transition in human melanoma cells.

The CD63 tetraspanin is highly expressed in the early stages of melanoma and decreases in advanced lesions, suggesting it as a possible suppressor of tumor progression. We employed loss- and gain-of-gene-function approaches to investigate the role of CD63 in melanoma progression and acquisition of the epithelial-to-mesenchymal transition (EMT) program. We used two human melanoma cell lines derived from primary tumors and one primary human melanoma cell line isolated from a cutaneous metastasis, differing by levels of CD63 expression.

Tetraspanin-enriched microdomains and hepatocellular carcinoma progression.

As in many tumors, heterogeneity within the cell population is one of the main features of hepatocellular carcinoma (HCC). Heterogeneity results from the ability of tumor to produce multiple subpopulations of cells with diverse genetic, biochemical and immunological characteristics. Little is known about how heterogeneity emerges and how it is maintained.

Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer death. Recent epidemiological data indicate that the mortality rate of HCC will double over the next decades in the USA and Europe. Liver cancer progresses in a large percentage of cases during the clinical course of chronic fibro-inflammatory liver diseases leading to cirrhosis.

The fibrotic microenvironment as a heterogeneity facet of hepatocellular carcinoma.

It has long been recognized that hepatocellular carcinoma heterogeneity arises from variation in the microenvironment or from genomic alteration. Only recently it has become clear that non-genetic alterations, such as cytoskeletal rearrangement, protein localization and formation of protein complexes, are also involved in generating phenotype variability. These proteome fluctuations cause genetically identical cells to vary significantly in their responsiveness to microenvironment stimuli.

Anticancer activity of an antisense oligonucleotide targeting TRADD combined with proteasome inhibitors in chemoresistant hepatocellular carcinoma cells.

Chemoresistance is a major cause of mortality of patients with advanced and metastatic hepatocellular carcinoma (HCC), the fifth most common cancer in the world. We employed a molecular approach to inhibit cell proliferation and induce apoptosis in HepG2 cells, originated from human hepatocarcinoma. TRADD gene expression was knocked down by an antisense oligonucleotide (ASO TRADD), resulting in TRADD protein decrease by 60%, coinciding with increase of apoptotic cell death of up to 30%.

Myristoylated Alanine-Rich protein Kinase C Substrate (MARCKS) expression modulates the metastatic phenotype in human and murine colon carcinoma in vitro and in vivo.

Several actin-binding proteins have been shown to be altered in metastatic cell lines and tumours and, in particular, Myristoylated Alanine-Rich protein Kinase C substrate (MARCKS) has been implicated in the pathogenesis of various highly metastatic epithelial malignancies. Considering that a large percentage of deaths due to colorectal cancer (CRC) are consequent to hepatic metastasization, aim of this study was to elucidate the involvement and mechanism of MARCKS in CRC by employing in vitro and in vivo approaches. Loss-of and-gain-on function approaches of MARCKS were employed in two human CRC cell lines: Clone A cells expressing MARCKS and LoVo cells known to have a frameshift mutation of MARCKS i.

Cell fusion promotes chemoresistance in metastatic colon carcinoma.

Chemoresistance is an important concern in the treatment of metastatic colon cancer. It may emerge through selection of clones that are inherently resistant from the outset or through mechanisms acquired during treatment. Cell fusion represents an efficient means of rapid phenotypic evolution that make cells with new properties at a rate exceeding that achievable by random mutagenesis.

The metastatic process: methodological advances and pharmacological challenges.

The metastatic spread of cancer is still the major barrier to the treatment of this disease. Understanding the molecular mechanisms underlying the metastatic process is of crucial importance to tune novel therapeutic strategies aimed at contrasting the dissemination of cancer. Metastasis is a sequential multistep process that ultimately leads to the cancer's outgrowth in a different organ from which it had originated.

Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma.

Background & Aims: Human hepatocellular carcinoma (HCC) can invade the portal vein and metastasize to other parts of the liver. Currently, the molecular and cellular mechanisms underlying intrahepatic metastasis of HCC are poorly understood. Tumor invasiveness could be considered an aspect of dysregulated motility, and the mechanisms that inhibit cell movement are considered to counteract the spreading of cancer cells through the liver.

MARCKS is a downstream effector in platelet-derived growth factor-induced cell motility in activated human hepatic stellate cells.

Myristoylated alanine-rich protein kinase c substrate (MARCKS) has been suggested to be implicated in cell adhesion, secretion, motility and mitogenesis through regulation of the actin cytoskeletal structure. In the present study, a possible link between MARCKS and the platelet-derived growth factor (PDGF) signaling pathway was investigated in activated human hepatic stellate cells (hHSC), critical regulators of hepatic fibrogenesis. PDGF-BB stimulation resulted in a bi-directional movement of MARCKS that coincided with the phosphorylation of MARCKS and the activation of both PKCepsilon and PKCalpha.

Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent.

Purpose: Treatment of hepatocellular carcinoma raised on cirrhotic liver represents a major endeavor because surgery and chemotherapeutic management fail to improve the clinical course of the disease. Chemoprevention could represent an important means to inhibit the process of hepatocarcinogenesis. Farnesyltransferase inhibitors are a class of drugs blocking the growth of tumor cells with minimal toxicity towards normal cells.

Signaling mechanisms that mediate invasion in prostate cancer cells.

Recent evidence indicates that androgen-sensitive prostate cancer cells have a less malignant phenotype characterized by reduced migration and invasion. We investigated whether the presence of the androgen receptor could affect EGFR-mediated signaling by evaluating autotransphosphorylation of the receptor as well as activation of the downstream signaling pathway PI3K/AKT. Immunoprecipitation studies demonstrated a reduction of EGF-induced tyrosine phosphorylation of EGFR in PC3-AR cells.

Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells.

The hepatitis C virus (HCV) envelope E2 glycoprotein is a key molecule regulating the interaction of HCV with cell surface proteins. E2 binds the major extracellular loop of human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Regardless, information on the biological functions originating from this interaction are largely unknown.

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen-sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR).

We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of alpha6beta4 integrin expression. The treatment with androgens further reduced invasion of the cells without modifying alpha6beta4 expression, suggesting an interference with the invasion process by androgens. Here, we investigated EGF-mediated signal transduction processes that lead to invasion in PC3-AR cells.

The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells.

Many recent evidences indicate that androgen-sensitive prostate cancer cells have a lower malignant phenotype that is in particular characterized by a reduced migration and invasion. We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of alpha6beta4 integrin expression. The treatment with the synthetic androgen R1881 further reduced invasion of the cells without, however, modifying alpha6beta4 expression on the cell surface, suggesting an interference with the invasion process in response to EGF.

Increased phosphorylation of AKAP by inhibition of phosphatidylinositol 3-kinase enhances human sperm motility through tail recruitment of protein kinase A.

Sperm motility is regulated by a complex balance between kinases and phosphatases. Among them, phosphatidylinositol 3-kinase (PI 3-kinase) has been recently suggested to negatively regulate sperm motility (Luconi, M., Marra, F.

Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells.

Tetraspanins is a large family of membrane proteins that are implicated in cell proliferation, differentiation and tumor invasion. Specifically, the tetraspanin CD81 has been involved in cell proliferation but the mechanism is unknown. Here, we show that CD81 clustering stimulates ERK/MAPKinase activity and tyrosine phosphorylation of the adapter protein Shc in Huh7 cancer cells.