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BBA - Reviews on Cancer (v.1815, #1)

Editorial Board (pp. i).

Gene regulation by SMAR1: Role in cellular homeostasis and cancer by Sunil Kumar Malonia; Surajit Sinha; Pavithra Lakshminarasimhan; Kamini Singh; Archana Jalota-Badhwar; Shravanti Rampalli; Ruchika Kaul-Ghanekar; Samit Chattopadhyay (pp. 1-12).
Changes in the composition of nuclear matrix associated proteins contribute to alterations in nuclear structure, one of the major phenotypes of malignant cancer cells. The malignancy-induced changes in this structure lead to alterations in chromatin folding, the fidelity of genome replication and gene expression programs. The nuclear matrix forms a scaffold upon which the chromatin is organized into periodic loop domains called matrix attachment regions (MAR) by binding to various MAR binding proteins (MARBPs). Aberrant expression of MARBPs modulates the chromatin organization and disrupt transcriptional network that leads to oncogenesis. Dysregulation of nuclear matrix associated MARBPs has been reported in different types of cancers. Some of these proteins have tumor specific expression and are therefore considered as promising diagnostic or prognostic markers in few cancers. SMAR1 (scaffold/matrix attachment region binding protein 1), is one such nuclear matrix associated protein whose expression is drastically reduced in higher grades of breast cancer. SMAR1 gene is located on human chromosome 16q24.3 locus, the loss of heterozygosity (LOH) of which has been reported in several types of cancers. This review elaborates on the multiple roles of nuclear matrix associated protein SMAR1 in regulating various cellular target genes involved in cell growth, apoptosis and tumorigenesis.

Keywords: SMAR1; Nuclear matrix; Chromatin; Apoptosis; Cell cycle; NF-κB


Connexins: sensors and regulators of cell cycling by Mathieu Vinken; Elke Decrock; Elke De Vuyst; Raf Ponsaerts; Catheleyne D'hondt; Geert Bultynck; Liesbeth Ceelen; Tamara Vanhaecke; Luc Leybaert; Vera Rogiers (pp. 13-25).
It is nowadays well established that gap junctions are critical gatekeepers of cell proliferation, by controlling the intercellular exchange of essential growth regulators. In recent years, however, it has become clear that the picture is not as simple as originally anticipated, as structural precursors of gap junctions can affect cell cycling by performing actions not related to gap junctional intercellular communication. Indeed, connexin hemichannels also foresee a pathway for cell growth communication, albeit between the intracellular compartment and the extracellular environment, while connexin proteins as such can directly or indirectly influence the production of cell cycle regulators independently of their channel activities. Furthermore, a novel set of connexin-like proteins, the pannexins, have lately joined in as regulators of the cell proliferation process, which they can affect as either single units or as channel entities. In the current paper, these multifaceted aspects of connexin-related signalling in cell cycling are reviewed.

Keywords: Abbreviations; AP-1; activator protein 1; ATP; adenosine triphosphate; cADPr; cyclic adenosine diphosphate ribose; cAMP; cyclic adenosine monophosphate; CCN; Cyr61, connective tissue growth factor (CTGF) and NOV; CD38; cluster of differentiation 38; cdk; cyclin-dependent kinase; Cip/Kip; cdk inhibitory protein/kinase inhibitor protein; Cx; connexin; CxRE; connexin response element; Cyr61; cysteine rich 61; Dlgh1; discs-large homolog; 1; EGF; epidermal growth factor; ERK1/2; extracellular regulated kinase 1/2; FGF1/2; fibroblast growth factor 1/2 (acidic/basic); G0/1/2 phase; gap 0/1/2 phase; GJIC; gap junctional intercellular communication; IP; 3; inositol trisphosphate; JNK; jun; NH; 2; terminal kinase; MAPK; mitogen-activated protein kinase; M phase; mitosis phase; NAD; +; nicotinamide adenine dinucleotide; NOV; nephroblastoma overexpressed; Panx; pannexin; PKC; protein kinase C; S phase; DNA synthesis phase; Skp2; S phase kinase-associated protein 2; Sp1; specificity protein 1; UDP; uridine diphosphate; Wnt; Wingless-Int; ZO-1/2; zonula occludens 1/2; ZONAB; ZO-1-associated nucleic acid binding proteinConnexin; Pannexin; Hemichannel; Gap junction; Cell cycle


NUMB-ing down cancer by more than just a NOTCH by Salvatore Pece; Stefano Confalonieri; Pascale R. Romano; Pier Paolo Di Fiore (pp. 26-43).
The protein Numb does not live up to its name. This passive-sounding protein is anything but spent. Originally identified as a cell-fate determinant in Drosophila development, Numb received a good deal of attention as an inhibitor of the Notch receptor signaling pathway. It turns out, however, that Numb does a lot more than simply regulate Notch. It has been implicated in a variety of biochemical pathways connected with signaling (it regulates Notch-, Hedgehog- and TP53-activated pathways), endocytosis (it is involved in cargo internalization and recycling), determination of polarity (it interacts with the PAR complex, and regulates adherens and tight junctions), and ubiquitination (it exploits this mechanism to regulate protein function and stability). This complex biochemical network lies at the heart of Numb's involvement in diverse cellular phenotypes, including cell fate developmental decisions, maintenance of stem cell compartments, regulation of cell polarity and adhesion, and migration. Considering its multifaceted role in cellular homeostasis, it is not surprising that Numb has been implicated in cancer as a tumor suppressor. Our major goal here is to explain the cancer-related role of Numb based on our understanding of its role in cell physiology. We will attempt to do this by reviewing the present knowledge of Numb at the biochemical and functional level, and by integrating its apparently heterogeneous functions into a unifying scenario, based on our recently proposed concept of the “endocytic matrix”. Finally, we will discuss the role of Numb in the maintenance of the normal stem cell compartment, as a starting point to interpret the tumor suppressor function of Numb in the context of the cancer stem cell hypothesis.

Keywords: Numb; Notch; Asymmetric cell division; Cancer; Stem cells; p53; Endocytosis


Current status of molecular markers for early detection of sporadic pancreatic cancer by Subhankar Chakraborty; Michael J. Baine; Aaron R. Sasson; Surinder K. Batra (pp. 44-64).
Pancreatic cancer (PC) is a highly lethal malignancy with near 100% mortality. This is in part due to the fact that most patients present with metastatic or locally advanced disease at the time of diagnosis. Significantly, in nearly 95% of PC patients there is neither an associated family history of PC nor of diseases known to be associated with an increased risk of PC. These groups of patients who comprise the bulk of PC cases are termed as “sporadic PC” in contrast to the familial PC cases that comprise only about 5% of all PCs. Given the insidious onset of the malignancy and its extreme resistance to chemo and radiotherapy, an abundance of research in recent years has focused on identifying biomarkers for the early detection of PC, specifically aiming at the sporadic PC cohort. However, while several studies have established that asymptomatic individuals with a positive family history of PC and those with certain heritable syndromes are candidates for PC screening, the role of screening in identifying sporadic PC is still an unsettled question. The present review attempts to assess this critical question by investigating the recent advances made in molecular markers with potential use in the early diagnosis of sporadic PC — the largest cohort of PC cases worldwide. It also outlines a novel yet simple risk factor based stratification system that could be potentially employed by clinicians to identify those individuals who are at an elevated risk for the development of sporadic PC and therefore candidates for screening.

Keywords: Diagnosis; PanIN; Biomarkers


Ribonucleases of different origins with a wide spectrum of medicinal applications by Evandro Fei Fang; Tzi Bun Ng (pp. 65-74).
Ribonucleases (RNases) are a type of nucleases that catalyze the degradation of RNA into smaller components. They exist in a wide range of life forms from prokaryotes to eukaryotes. RNase-controlled RNA degradation is a determining factor in the control of gene expression, maturation and turnover, which are further associated with the progression of cancers and infectious diseases. Over the years, RNases purified from multiple origins have drawn increasing attention from medical scientists due to their remarkable antitumor properties. In this review, we present a brief summary of the representative RNases of fungal, bacterial, plant, and animal origins and outline their potential medicinal value in the treatment of tumor and AIDS. Among them, the most clinically promising RNases are mushroom RNases, Binase and Barnase from bacteria, ginseng RNases, and Onconase from frog ( Rana pipiens). Fast developing protein engineering of RNases, which display more potent cytotoxic activity on and greater selectivity for malignant cells, has also aroused the interest of researchers. The multiple anti-cancer mechanisms of RNases are also included. To sum up, these inspiring studies unveil a new perspective for RNases as potential therapeutic agents.

Keywords: Ribonuclease; Tumor; Mushroom; Binase; Onconase; Ginseng


Histone lysine methylation and demethylation pathways in cancer by Radhika A. Varier; H.T. Marc Timmers (pp. 75-89).
The genetic changes leading to the development of human cancer are accompanied by alterations in the structure and modification status of chromatin, which represent powerful regulatory mechanisms for gene expression and genome stability. These epigenetic alterations have sparked interest into deciphering the regulatory pathways and function of post-translational modifications of histones during the initiation and progression of cancer. In this review we describe and summarize the current knowledge of several histone lysine methyltransferase and demethylase pathways relevant to cancer. Mechanistic insight into histone modifications will pave the way for the development and therapeutic application of “epidrugs” in cancer.

Keywords: Histone methylation; Menin; Cancer; Epigenetics; Epidrugs; Chromatin


NFκB/p53 crosstalk—a promising new therapeutic target by Günter Schneider; Kramer Oliver H. Krämer (pp. 90-103).
The transcription factors p53 and NFκB determine cellular fate and are involved in the pathogenesis of most–if not all–cancers. The crosstalk between these transcription factors becomes increasingly appreciated as an important mechanism operative during all stages of tumorigenesis, metastasis, and immunological surveillance. In this review, we summarize molecular mechanisms regulating cross-signaling between p53 and NFκB proteins and how dysregulated interactions between p53 and NFκB family members contribute to oncogenesis. We furthermore analyze how such signaling modules represent targets for the design of novel intervention strategies using established compounds and powerful combination therapies.

Keywords: Abbreviations; AD; activation domain; AKT; cellular homolog of murine thymoma virus akt8 oncogene, serine/threonine kinase B; AML; acute myeloid leukemia; AP-1; JUN/FOS transcription factor; ATM; ataxia telangiectasia mutated; ATR; ATM- and RAD3-related; ARD; ankyrin repeat domain; ARF; alternate reading frame of the INK4a/ARF locus; α5/β1; integrin α5/β1; BAFF; B-cell-activating factor; BAX; BCL-2-associated X protein; BCL; B cell lymphoma; BH3; BCL-2 homology domain 3; CDK; cyclin-dependent kinase; CHK1; checkpoint kinase 1; CHK2; checkpoint kinase 2; CHUK; conserved helix-loop-helix ubiquitous kinase; CK2; casein kinase 2; COP1; caspase recruitment domain family, member 16; CTD; C-terminal domain; DBD; DNA-binding domain; DDR; DNA damage response; dsB; double strand breaks; EGCG; epigallocatechin-3-gallate poly-phenol; EGF; EGFR ligand; EGFR; epidermal growth factor receptor; EGR1; early growth response 1; EMT; epithelial-mesenchymal transition; ERK; extracellular regulated kinase; E1; ubiquitin-activating enzyme; E2; ubiquitin-conjugase; E3; ubiquitin-ligase; FAK; non-receptor focal adhesion kinase; FAS; TNF-receptor superfamily, member 6 (CD95, APO-1); FASL; FAS-ligand; GLUT; glucose transporter; HAT; histone acetyltransferase; HB-EGF; Heparin-binding EGF-like growth factor; HCC; hepatocellular carcinoma; HDACI; histone deacetylase inhibitor; HDAC; histone deacetylase; HDM2; human double minute ubiquitin ligase; HNSCC; head and neck squamous cell carcinoma; HU; hydroxyurea; ICAM; intracellular adhesion molecule; IκB; NFκB inhibitory proteins; IKK; IκB kinase; IL-1; interleukin-1; JAK; Janus kinase; KAI1/CD82; cluster of differentiation 82; LTβ; lymphotoxin-β; LPA; lysophosphatidic acid; MCP; monocyte chemoattractant protein; MDM2; murine double minute (ubiquitin ligase); MEK; Mitogen-activated protein kinase kinase; MMP; matrix metalloproteinase; MnSOD; superoxide dismutase 2, mitochondrial; NEMO; NFκB essential modulator; NLS; nuclear localization signal; NFκB; nuclear factor 'kappa-light-chain-enhancer' of activated B-cells; NIK; NFκB inducing kinase; p53-AIP1; p53-regulated Apoptosis-Inducing Protein 1; PAT; protein acetyltransferase; PDAC; protein deacetylase; PC; prostate carcinoma; PI3K; phosphatidylinositol 3-kinase inhibitor; PPase; phosphatase; PAI1; senescence regulator; PAMPs; pathogen associated molecular patterns; PARP; poly(ADP-ribose)-polymerase; PDGF-A; platelet-derived growth factor; PIASy; protein inhibitor y of activated STAT; PIDD; p53-induced protein with death domain; PIRH2; p53-induced ubiquitin-protein ligase; PRD; proline rich domain; PUMA; p53 upregulated modulator of apoptosis; p21; cyclin-dependent kinase inhibitor 21; kDa; p53; tumor suppressor protein 53; kDa; p63; p53 homologue 63; kDa; p73; p53 homologue 73; kDa; RCP; RAB-coupling protein; RSK; ribosomal serine/threonine kinase; RIP; receptor interacting protein; Rel v-rel; reticuloendotheliosis viral oncogene homolog (A, avian); RHD; Rel-homology domain; ROS; reactive oxygen species; SCF; ubiquitin ligase complex of Skp1/Cul1/Rbx1/F-box proteinβ-TrCP1; SHP; SH2 domain containing phosphatase; SUMO; small ubiquitin-like modifier; ssB; single strand breaks; SIRT; silencing information regulator; SNAIL; C2H2-type zinc finger transcription factor; STAT; signal transducer and activator of transcription; TAD; transcriptional activation domain; TGFβ; transforming growth factor β; TIGAR; TP53-induced glycolysis and apoptosis regulator; TNFα; tumor necrosis factor-α; TRAF; TNF receptor associated factor; TRIM24; Tripartite motif-containing 24 (TRIM24), transcriptional intermediary factor 1α; ZEB1/ZEB2; zinc finger E-box binding transcription factorsRelA/p65; NFκB; p53; Signaling; Therapy; Cancer


The role of Stat5 transcription factors as tumor suppressors or oncogenes by G. Ferbeyre; R. Moriggl (pp. 104-114).
Stat5 is constitutively activated in many human cancers affecting the expression of cell proliferation and cell survival controlling genes. These oncogenic functions of Stat5 have been elegantly reproduced in mouse models. Aberrant Stat5 activity induces also mitochondrial dysfunction and reactive oxygen species leading to DNA damage. Although DNA damage can stimulate tumorigenesis, it can also prevent it. Stat5 can inhibit tumor progression like in the liver and it is a tumor suppressor in fibroblasts. Stat5 proteins are able to regulate cell differentiation and senescence activating the tumor suppressors SOCS1, p53 and PML. Understanding the context dependent regulation of tumorigenesis through Stat5 function will be central to understand proliferation, survival, differentiation or senescence of cancer cells.

Keywords: Stat5; Jak–Stat signaling; Senescence; Mouse models


Estrogen-induced reactive oxygen species-mediated signalings contribute to breast cancer by Victor Okoh; Alok Deoraj; Deodutta Roy (pp. 115-133).
Elevated lifetime estrogen exposure is a major risk factor for breast cancer. Recent advances in the understanding of breast carcinogenesis clearly indicate that induction of estrogen receptor (ER) mediated signaling is not sufficient for the development of breast cancer. The underlying mechanisms of breast susceptibility to estrogen's carcinogenic effect remain elusive. Physiologically achievable concentrations of estrogen or estrogen metabolites have been shown to generate reactive oxygen species (ROS). Recent data implicated that these ROS induced DNA synthesis, increased phosphorylation of kinases, and activated transcription factors, e.g., AP-1, NRF1, E2F, NF-kB and CREB of non-genomic pathways which are responsive to both oxidants and estrogen. Estrogen-induced ROS by increasing genomic instability and by transducing signal through influencing redox sensitive transcription factors play important role (s) in cell transformation, cell cycle, migration and invasion of the breast cancer. The present review discusses emerging data in support of the role of estrogen induced ROS-mediated signaling pathways which may contribute in the development of breast cancer. It is envisioned that estrogen induced ROS mediated signaling is a key complementary mechanism that drives the carcinogenesis process. ROS mediated signaling however occurs in the context of other estrogen induced processes such as ER-mediated signaling and estrogen reactive metabolite-associated genotoxicity. Importantly, estrogen-induced ROS can function as independent reversible modifiers of phosphatases and activate kinases to trigger the transcription factors of downstream target genes which participate in cancer progression.

Keywords: ROS; Estrogen; Signal transduction; Breast cancer
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