|
|
BBA - Reviews on Cancer (v.1816, #1)
Uncovering the role of hypoxia inducible factor-1α in skin carcinogenesis
by Kris Nys; Hannelore Maes; Aleksandra Maria Dudek; Patrizia Agostinis (pp. 1-12).
The hypoxia inducible factor-1α (HIF-1α) is a pleiotropic transcription factor typically activated in response to low oxygen tension as well as other stress factors in normoxic conditions. Upon activation HIF-1α mediates the transcriptional activation of target genes involved in a variety of processes comprising stress adaptation, metabolism, growth and invasion, but also apoptotic cell death. The molecular mechanisms, signaling pathways and downstream targets evoked by the activation of HIF-1α in epidermal cells are becoming increasingly understood and underscore the participation of HIF-1α in crucial processes including malignant transformation and cancer progression. Recent studies have implicated HIF-1α as an integral part of the multifaceted signal transduction initiated by the exposure of keratinocytes to ultraviolet radiation B (UVB), which represents the most ubiquitous hazard for human skin and the principal risk factor for skin cancer. HIF-1α activation by UVB exposure contributes to either repair or the removal of UVB-damaged keratinocytes by inducing apoptosis, thus revealing a tumor suppressor role for HIF-1α in these cells. On the other hand, the constitutive expression of HIF-1α evoked by the mild hypoxic state of the skin has been implicated as a positive factor in the transformation of normal melanocytes into malignant melanoma, one of the most aggressive types of human cancers. Here we review the uncovered and complex role of HIF-1α in skin carcinogenesis.
Keywords: Abbreviations; Bax; Bcl-2-associated X protein; BCC; Basal cell carcinoma; Bcl-2; B cell lymphoma; Bcl-x; L; B-cell lymphoma-extra large; BNIP3; BCL2/adenovirus E1B 19; kDa protein-interacting protein 3; CMM; Cutaneous malignant melanoma; CBP; cyclic-AMP response element binding protein (CREB) binding protein; CPDs; Cyclobutane pyrimidine dimers; HIF-1; Hypoxia inducible factor 1; HRE; Hypoxia response element; MAPK; Mitogen activated protein kinase; MEF; Mouse embryonal fibroblast; MITF; Microphthalmia-associated transcription factor; mTOR; Mammalian target of rapamycin; NDRG1; N-myc downstream regulated gene-1; PHD; Prolyl hydroxylase; PI3K; Phosphatidyl inositol-3 kinase; ROS; Reactive oxygen species; SBC; Sunburn cell; SCC; Squamous cell carcinoma; Selenbp1; Selenium binding protein-1; Siah2; Seven of absentia homologue 2; Spry2; Sprouty 2; UV; UltraViolet; VEGF; Vascular endothelial growth factorHIF-1α; UVB; Mild hypoxia; Skin cancer; Keratinocytes; Melanocytes; Apoptosis; Carcinogenesis; CMM; SCC
Uncovering the role of hypoxia inducible factor-1α in skin carcinogenesis
by Kris Nys; Hannelore Maes; Aleksandra Maria Dudek; Patrizia Agostinis (pp. 1-12).
The hypoxia inducible factor-1α (HIF-1α) is a pleiotropic transcription factor typically activated in response to low oxygen tension as well as other stress factors in normoxic conditions. Upon activation HIF-1α mediates the transcriptional activation of target genes involved in a variety of processes comprising stress adaptation, metabolism, growth and invasion, but also apoptotic cell death. The molecular mechanisms, signaling pathways and downstream targets evoked by the activation of HIF-1α in epidermal cells are becoming increasingly understood and underscore the participation of HIF-1α in crucial processes including malignant transformation and cancer progression. Recent studies have implicated HIF-1α as an integral part of the multifaceted signal transduction initiated by the exposure of keratinocytes to ultraviolet radiation B (UVB), which represents the most ubiquitous hazard for human skin and the principal risk factor for skin cancer. HIF-1α activation by UVB exposure contributes to either repair or the removal of UVB-damaged keratinocytes by inducing apoptosis, thus revealing a tumor suppressor role for HIF-1α in these cells. On the other hand, the constitutive expression of HIF-1α evoked by the mild hypoxic state of the skin has been implicated as a positive factor in the transformation of normal melanocytes into malignant melanoma, one of the most aggressive types of human cancers. Here we review the uncovered and complex role of HIF-1α in skin carcinogenesis.
Keywords: Abbreviations; Bax; Bcl-2-associated X protein; BCC; Basal cell carcinoma; Bcl-2; B cell lymphoma; Bcl-x; L; B-cell lymphoma-extra large; BNIP3; BCL2/adenovirus E1B 19; kDa protein-interacting protein 3; CMM; Cutaneous malignant melanoma; CBP; cyclic-AMP response element binding protein (CREB) binding protein; CPDs; Cyclobutane pyrimidine dimers; HIF-1; Hypoxia inducible factor 1; HRE; Hypoxia response element; MAPK; Mitogen activated protein kinase; MEF; Mouse embryonal fibroblast; MITF; Microphthalmia-associated transcription factor; mTOR; Mammalian target of rapamycin; NDRG1; N-myc downstream regulated gene-1; PHD; Prolyl hydroxylase; PI3K; Phosphatidyl inositol-3 kinase; ROS; Reactive oxygen species; SBC; Sunburn cell; SCC; Squamous cell carcinoma; Selenbp1; Selenium binding protein-1; Siah2; Seven of absentia homologue 2; Spry2; Sprouty 2; UV; UltraViolet; VEGF; Vascular endothelial growth factorHIF-1α; UVB; Mild hypoxia; Skin cancer; Keratinocytes; Melanocytes; Apoptosis; Carcinogenesis; CMM; SCC
Unknown primary tumors
by C. Natoli; V. Ramazzotti; O. Nappi; P. Giacomini; S. Palmeri; M. Salvatore; M. Landriscina; M. Zilli; P.G. Natali; N. Tinari; S. Iacobelli (pp. 13-24).
An unknown primary tumor (UPT) is defined by the presence of a metastatic cancer without a known primary site of origin despite a standardized diagnostic workup. Clinically, UPTs show rapid progression and early dissemination, with signs and symptoms related to the metastatic site. The molecular bases of their biology remain largely unknown, with no evidence as to whether they represent a distinct biological entity.Immunohistochemistry remain the best diagnostic tool in term of cost-effectiveness, but the time-consuming “algorithmic process” it relies on has led to the application of new molecular techniques for the identification of the primary site of UPTs. For example, several microarray or miRNA classifications of UPTs have been used, with an accuracy in the prediction of the primary site as high as 90%. It should be noted that validating a prediction of tissue origin is challenging in these patients, since most of them will never have a primary site identified. Moreover, prospective studies to determine whether selection of treatment options based on such profiling methods actually improves patient outcome are still missing. In the last few years functional imaging (i.e. FDG-PET/CT) has gained a main role in the detection of the site of origin of UPTs and is currently recommended by the European Association of Nuclear Medicine. However, despite recent refinements in the diagnostic workup, the site of origin of UPT often remains elusive. As a consequence, treatment of patients with UPT is still empirical and inadequate.
Keywords: Abbreviations; αFP; alpha-fetoprotein; βHCG; human chorionic gonadotropin; CA; cytosine-adenosine; CEA; carcinoembryonic antigen; CK; cytokeratin; EGFR; epidermal growth factor receptor; ECM; extracellular matrix; EANM; European Association of Nuclear Medicine; FFPE; formalin-fixed, paraffin-embedded; FDG; 18F-fluorodeoxyglucose; FU; fluorouracil; HBV; hepatitis B; HCV; hepatitis C; IHC; immunohistochemistry; miRNA; microRNA; MMP; matrix metalloproteinase; mRNA; messenger RNA; MVD; microvessel density; NET; neuroendocrine tumors; NOS; not otherwise specified; NSCLC; non-small cell lung cancer; OS; overall survival; PET; positron emission tomography; PLAP; placental alkaline phosphatase; PSA; prostate specific antigen; pts; patients; RR; response rate; RT-PCR; reverse transcription polymerase chain reaction; SPET; photon emission tomography; SVM; microarray support vector machine; CT; computed tomography; TIMPs; tissue inhibitor of metalloproteinases; TSP1; thrombospondin-1; TTF-1; thyroid transcription factor-1; UPT; unknown primary tumor; VEGF; vascular endothelial growth factorUnknown primary tumor; Unknown primary site; Carcinoma of unknown primary; Undetermined primary site; Occult primary tumor
Unknown primary tumors
by C. Natoli; V. Ramazzotti; O. Nappi; P. Giacomini; S. Palmeri; M. Salvatore; M. Landriscina; M. Zilli; P.G. Natali; N. Tinari; S. Iacobelli (pp. 13-24).
An unknown primary tumor (UPT) is defined by the presence of a metastatic cancer without a known primary site of origin despite a standardized diagnostic workup. Clinically, UPTs show rapid progression and early dissemination, with signs and symptoms related to the metastatic site. The molecular bases of their biology remain largely unknown, with no evidence as to whether they represent a distinct biological entity.Immunohistochemistry remain the best diagnostic tool in term of cost-effectiveness, but the time-consuming “algorithmic process” it relies on has led to the application of new molecular techniques for the identification of the primary site of UPTs. For example, several microarray or miRNA classifications of UPTs have been used, with an accuracy in the prediction of the primary site as high as 90%. It should be noted that validating a prediction of tissue origin is challenging in these patients, since most of them will never have a primary site identified. Moreover, prospective studies to determine whether selection of treatment options based on such profiling methods actually improves patient outcome are still missing. In the last few years functional imaging (i.e. FDG-PET/CT) has gained a main role in the detection of the site of origin of UPTs and is currently recommended by the European Association of Nuclear Medicine. However, despite recent refinements in the diagnostic workup, the site of origin of UPT often remains elusive. As a consequence, treatment of patients with UPT is still empirical and inadequate.
Keywords: Abbreviations; αFP; alpha-fetoprotein; βHCG; human chorionic gonadotropin; CA; cytosine-adenosine; CEA; carcinoembryonic antigen; CK; cytokeratin; EGFR; epidermal growth factor receptor; ECM; extracellular matrix; EANM; European Association of Nuclear Medicine; FFPE; formalin-fixed, paraffin-embedded; FDG; 18F-fluorodeoxyglucose; FU; fluorouracil; HBV; hepatitis B; HCV; hepatitis C; IHC; immunohistochemistry; miRNA; microRNA; MMP; matrix metalloproteinase; mRNA; messenger RNA; MVD; microvessel density; NET; neuroendocrine tumors; NOS; not otherwise specified; NSCLC; non-small cell lung cancer; OS; overall survival; PET; positron emission tomography; PLAP; placental alkaline phosphatase; PSA; prostate specific antigen; pts; patients; RR; response rate; RT-PCR; reverse transcription polymerase chain reaction; SPET; photon emission tomography; SVM; microarray support vector machine; CT; computed tomography; TIMPs; tissue inhibitor of metalloproteinases; TSP1; thrombospondin-1; TTF-1; thyroid transcription factor-1; UPT; unknown primary tumor; VEGF; vascular endothelial growth factorUnknown primary tumor; Unknown primary site; Carcinoma of unknown primary; Undetermined primary site; Occult primary tumor
Animal models relevant to human prostate carcinogenesis underlining the critical implication of prostatic stem/progenitor cells
by Murielle Mimeault; Surinder K. Batra (pp. 25-37).
Recent development of animal models relevant to human prostate cancer (PC) etiopathogenesis has provided important information on the specific functions provided by key gene products altered during disease initiation and progression to locally invasive, metastatic and hormone-refractory stages. Especially, the characterization of transgenic mouse models has indicated that the inactivation of distinct tumor suppressor proteins such as phosphatase tensin homolog deleted on chromosome 10 (PTEN), Nkx3.1, p27KIP1, p53 and retinoblastoma (pRb) may cooperate for the malignant transformation of prostatic stem/progenitor cells into PC stem/progenitor cells and tumor development and metastases. Moreover, the sustained activation of diverse oncogenic signaling elements, including epidermal growth factor receptor (EGFR), sonic hedgehog, Wnt/β-catenin, c-Myc, Akt and nuclear factor-kappaB (NF-κB) also may contribute to the acquisition of more aggressive and hormone-refractory phenotypes by PC stem/progenitor cells and their progenies during disease progression. Importantly, it has also been shown that an enrichment of PC stem/progenitor cells expressing stem cell-like markers may occur after androgen deprivation therapy and docetaxel treatment in the transgenic mouse models of PC suggesting the critical implication of these immature PC cells in treatment resistance, tumor re-growth and disease recurrence. Of clinical interest, the molecular targeting of distinct gene products altered in PC cells by using different dietary compounds has also been shown to counteract PC initiation and progression in animal models supporting their potential use as chemopreventive or chemotherapeutic agents for eradicating the total tumor cell mass, improving current anti-hormonal and chemotherapies and preventing disease relapse.
Keywords: Abbreviations; ADT; androgen deprivation therapy; AI; androgen-independent; ALDH; aldehyde dehydrogenase; AR; androgen receptor; ARR; 2; two androgen-responsive regions; BM; bone marrow; CXCR4; CXC chemokine receptor 4; CK; cytokeratin; ECM; extracellular matrix; EGFR; epidermal growth factor receptor; EMT; epithelial–mesenchymal transition; FGF; fibroblast growth factor; HIF-1α; hypoxia-inducible factor-1α HRPCs, hormone-refractory prostate cancers; IGF; insulin-like growth factor; IL-6; interleukin-6; MAPKs; mitogen-activated protein kinases; MMPs; matrix metalloproteinases; NOD/SCID; nonobese diabetic/severe combined immunodeficient; NE; neuroendocrine; NF-κB; nuclear factor-kappaB; Nrf2; nuclear factor (erythroid-derived 2)-like 2; PB; probasin; PC; prostate cancer; PI3K; phosphatidylinositol 3′-kinase; PINs; prostatic intraepithelial neoplasms; PIP3; phosphatidylinositol 3,4,5-trisphosphate; PRL; prolactin; PTEN; phosphatase tensin homolog deleted on chromosome 10; pRb; retinoblastoma protein; Sca-1; stem cell antigen-1; SDF-1; stromal cell-derived factor-1; SHH; sonic hedgehog; STAT; signal transducer and activator of transcription; SV40; simian virus 40; Tag; antigen-coding region; TGF-β; transforming growth factor-β; TRAMP; transgenic adenocarcinoma of the mouse prostate; UGSM; urogenital sinus mesenchymal; uPA; urokinase-type plasminogen activator; VEGF; vascular endothelial growth factorProstate cancer; Metastases; Transgenic mouse models; Prostatic cancer stem/progenitor cells; PTEN; Akt; Dietary compounds; Chemopreventive treatments; Combination therapy
Animal models relevant to human prostate carcinogenesis underlining the critical implication of prostatic stem/progenitor cells
by Murielle Mimeault; Surinder K. Batra (pp. 25-37).
Recent development of animal models relevant to human prostate cancer (PC) etiopathogenesis has provided important information on the specific functions provided by key gene products altered during disease initiation and progression to locally invasive, metastatic and hormone-refractory stages. Especially, the characterization of transgenic mouse models has indicated that the inactivation of distinct tumor suppressor proteins such as phosphatase tensin homolog deleted on chromosome 10 (PTEN), Nkx3.1, p27KIP1, p53 and retinoblastoma (pRb) may cooperate for the malignant transformation of prostatic stem/progenitor cells into PC stem/progenitor cells and tumor development and metastases. Moreover, the sustained activation of diverse oncogenic signaling elements, including epidermal growth factor receptor (EGFR), sonic hedgehog, Wnt/β-catenin, c-Myc, Akt and nuclear factor-kappaB (NF-κB) also may contribute to the acquisition of more aggressive and hormone-refractory phenotypes by PC stem/progenitor cells and their progenies during disease progression. Importantly, it has also been shown that an enrichment of PC stem/progenitor cells expressing stem cell-like markers may occur after androgen deprivation therapy and docetaxel treatment in the transgenic mouse models of PC suggesting the critical implication of these immature PC cells in treatment resistance, tumor re-growth and disease recurrence. Of clinical interest, the molecular targeting of distinct gene products altered in PC cells by using different dietary compounds has also been shown to counteract PC initiation and progression in animal models supporting their potential use as chemopreventive or chemotherapeutic agents for eradicating the total tumor cell mass, improving current anti-hormonal and chemotherapies and preventing disease relapse.
Keywords: Abbreviations; ADT; androgen deprivation therapy; AI; androgen-independent; ALDH; aldehyde dehydrogenase; AR; androgen receptor; ARR; 2; two androgen-responsive regions; BM; bone marrow; CXCR4; CXC chemokine receptor 4; CK; cytokeratin; ECM; extracellular matrix; EGFR; epidermal growth factor receptor; EMT; epithelial–mesenchymal transition; FGF; fibroblast growth factor; HIF-1α; hypoxia-inducible factor-1α HRPCs, hormone-refractory prostate cancers; IGF; insulin-like growth factor; IL-6; interleukin-6; MAPKs; mitogen-activated protein kinases; MMPs; matrix metalloproteinases; NOD/SCID; nonobese diabetic/severe combined immunodeficient; NE; neuroendocrine; NF-κB; nuclear factor-kappaB; Nrf2; nuclear factor (erythroid-derived 2)-like 2; PB; probasin; PC; prostate cancer; PI3K; phosphatidylinositol 3′-kinase; PINs; prostatic intraepithelial neoplasms; PIP3; phosphatidylinositol 3,4,5-trisphosphate; PRL; prolactin; PTEN; phosphatase tensin homolog deleted on chromosome 10; pRb; retinoblastoma protein; Sca-1; stem cell antigen-1; SDF-1; stromal cell-derived factor-1; SHH; sonic hedgehog; STAT; signal transducer and activator of transcription; SV40; simian virus 40; Tag; antigen-coding region; TGF-β; transforming growth factor-β; TRAMP; transgenic adenocarcinoma of the mouse prostate; UGSM; urogenital sinus mesenchymal; uPA; urokinase-type plasminogen activator; VEGF; vascular endothelial growth factorProstate cancer; Metastases; Transgenic mouse models; Prostatic cancer stem/progenitor cells; PTEN; Akt; Dietary compounds; Chemopreventive treatments; Combination therapy
Signal transducers and activators of transcription—from cytokine signalling to cancer biology
by Cristina Isabel Santos; Ana P. Costa-Pereira (pp. 38-49).
Signal transducers and activators of transcription (STATs) are, as the name indicates, both signal transducers and transcription factors. STATs are activated by cytokines and some growth factors and thus control important biological processes. These include cell growth, cell differentiation, apoptosis and immune responses. Dysregulation of STATs, either due to constitutive activation or function impairment, can have, therefore, deleterious biological consequences. This review places particular emphasis on their structural organization, biological activities and regulatory mechanisms most commonly utilized by cells to control STAT-mediated signalling. STATs also play important roles in cancer and immune deficiencies and are thus being exploited as therapeutic targets.
Keywords: JAK; STAT; Signalling; Interferons; Cytokines; Cancer
Signal transducers and activators of transcription—from cytokine signalling to cancer biology
by Cristina Isabel Santos; Ana P. Costa-Pereira (pp. 38-49).
Signal transducers and activators of transcription (STATs) are, as the name indicates, both signal transducers and transcription factors. STATs are activated by cytokines and some growth factors and thus control important biological processes. These include cell growth, cell differentiation, apoptosis and immune responses. Dysregulation of STATs, either due to constitutive activation or function impairment, can have, therefore, deleterious biological consequences. This review places particular emphasis on their structural organization, biological activities and regulatory mechanisms most commonly utilized by cells to control STAT-mediated signalling. STATs also play important roles in cancer and immune deficiencies and are thus being exploited as therapeutic targets.
Keywords: JAK; STAT; Signalling; Interferons; Cytokines; Cancer
The hallmarks of CDKN1C (p57, KIP2) in cancer
by Edel Kavanagh; Bertrand Joseph (pp. 50-56).
Cyclin-dependent kinase inhibitor 1C CDKN1C (p57KIP2) regulates several hallmarks of cancer, including apoptosis, cell invasion and metastasis, tumor differentiation and angiogenesis. p57KIP2 is generally not mutated in cancer, but its expression is downregulated through epigenetic changes such as DNA methylation and repressive histone marks at the promoter. This opens up possibilities for therapeutic intervention through reactivation of p57KIP2 gene expression. Furthermore, p57KIP2 has been tested as a prognostic factor for many types of cancer, even differentiating between early and late stage cancer. In this review, the multifunctional tumor suppressor capabilities of p57KIP2, the mechanisms of p57KIP2 transcriptional repression in cancer, and the therapeutic potential of reactivation of p57KIP2 protein expression will be discussed.
Keywords: Abbreviations; AML; acute myeloid leukemia; Bcl-2; B-cell lymphoma 2; Bcl-xL; B-cell lymphoma-x long; BCR-ABL; breakpoint cluster region-V-abl Abelson murine leukemia viral oncogene homolog 1; bHLH; basic helix–loop–helix; BWS; Beckwith–Wiedemann Syndrome; CDK; cyclin-dependent kinase; CIP/KIP; CDK interacting protein/kinase inhibitory protein; CDKN1C; cyclin dependent kinase 1C; CML; chromic myeloid leukemia; CpG; cytosine-phosphate-guanine; DLCBL; diffuse large B cell lymphoma; DNA; deoxyribonucleic acid; EGCG; epigallocatechin-3-gallate; ES cells; embryonic stem cells; EZH2; Enhancer of Zeste homolog 2; HDAC; histone deacetylase; Hes1; hairy and enhancer of split 1; IGF2; insulin growth factor 2; JNK; c-Jun N-terminal kinase; LIMK1; LIM domain kinase 1; Mash1; mammalian achate schute Homolog 1; miRNA; micro-ribonucleic acid; MyoD; myogenic differentiation; PACAP; pituitary adenylate cyclase activating polypeptide; PAPA; proline–alanine–proline–alanine; ROCK; Rho-associated protein kinase; SAHA; suberoylanilide hydroxamic acid; SCF; Skp1/Cul1/F-box; SKP2; S-phase kinase-associated protein 2; UV; ultraviolet; VEGF; vascular endothelial growth factorp57; KIP2; Cancer; Tumor suppressor
The hallmarks of CDKN1C (p57, KIP2) in cancer
by Edel Kavanagh; Bertrand Joseph (pp. 50-56).
Cyclin-dependent kinase inhibitor 1C CDKN1C (p57KIP2) regulates several hallmarks of cancer, including apoptosis, cell invasion and metastasis, tumor differentiation and angiogenesis. p57KIP2 is generally not mutated in cancer, but its expression is downregulated through epigenetic changes such as DNA methylation and repressive histone marks at the promoter. This opens up possibilities for therapeutic intervention through reactivation of p57KIP2 gene expression. Furthermore, p57KIP2 has been tested as a prognostic factor for many types of cancer, even differentiating between early and late stage cancer. In this review, the multifunctional tumor suppressor capabilities of p57KIP2, the mechanisms of p57KIP2 transcriptional repression in cancer, and the therapeutic potential of reactivation of p57KIP2 protein expression will be discussed.
Keywords: Abbreviations; AML; acute myeloid leukemia; Bcl-2; B-cell lymphoma 2; Bcl-xL; B-cell lymphoma-x long; BCR-ABL; breakpoint cluster region-V-abl Abelson murine leukemia viral oncogene homolog 1; bHLH; basic helix–loop–helix; BWS; Beckwith–Wiedemann Syndrome; CDK; cyclin-dependent kinase; CIP/KIP; CDK interacting protein/kinase inhibitory protein; CDKN1C; cyclin dependent kinase 1C; CML; chromic myeloid leukemia; CpG; cytosine-phosphate-guanine; DLCBL; diffuse large B cell lymphoma; DNA; deoxyribonucleic acid; EGCG; epigallocatechin-3-gallate; ES cells; embryonic stem cells; EZH2; Enhancer of Zeste homolog 2; HDAC; histone deacetylase; Hes1; hairy and enhancer of split 1; IGF2; insulin growth factor 2; JNK; c-Jun N-terminal kinase; LIMK1; LIM domain kinase 1; Mash1; mammalian achate schute Homolog 1; miRNA; micro-ribonucleic acid; MyoD; myogenic differentiation; PACAP; pituitary adenylate cyclase activating polypeptide; PAPA; proline–alanine–proline–alanine; ROCK; Rho-associated protein kinase; SAHA; suberoylanilide hydroxamic acid; SCF; Skp1/Cul1/F-box; SKP2; S-phase kinase-associated protein 2; UV; ultraviolet; VEGF; vascular endothelial growth factorp57; KIP2; Cancer; Tumor suppressor
Role of p63 in cancer development
by Vincenzo Graziano; Vincenzo De Laurenzi (pp. 57-66).
Since their initial identification p53 homologues p63 and p73 have been expected to play a role in cancer development due to their close homology to p53, notoriously one of the most mutated genes in cancer. However soon after their discovery the awareness that these genes were rarely mutated in cancer seemed to indicate that they did not play a role in its development. However a large number of data collected in the following years indicated that altered expression rather than mutation could be found in different neoplasia and play a role in its biology. In particular p63 due to its fundamental role in epithelial development seems to play a role in a number of tumors of epithelial origin. In this review we summarize some of the evidence linking p63 to carcinogenesis.
Keywords: p63; Oncogenes; Oncosuppressors; Cancerogenesis; Molecular biology
Role of p63 in cancer development
by Vincenzo Graziano; Vincenzo De Laurenzi (pp. 57-66).
Since their initial identification p53 homologues p63 and p73 have been expected to play a role in cancer development due to their close homology to p53, notoriously one of the most mutated genes in cancer. However soon after their discovery the awareness that these genes were rarely mutated in cancer seemed to indicate that they did not play a role in its development. However a large number of data collected in the following years indicated that altered expression rather than mutation could be found in different neoplasia and play a role in its biology. In particular p63 due to its fundamental role in epithelial development seems to play a role in a number of tumors of epithelial origin. In this review we summarize some of the evidence linking p63 to carcinogenesis.
Keywords: p63; Oncogenes; Oncosuppressors; Cancerogenesis; Molecular biology
A miR-centric view of head and neck cancers
by Janki Mohan Babu; R. Prathibha; V.S. Jijith; Ramkumar Hariharan; M. Radhakrishna Pillai (pp. 67-72).
Head and Neck Squamous Cell Carcinomas (HNSCCs) constitute the sixth most common cancer worldwide with an average 5-year survival rate of around 50%. Several microRNAs, small non-coding RNAs involved in post-transcriptional gene regulation, have been linked to HNSCC based on their differential expression in tumors. Here, we present a compilation of multiple types of information on each HNSCC linked miRNA including their expression status in tumors, their molecular targets relevant to cancer, results of gene manipulation studies and association with clinical outcome. Further, we use this information to devise a new scheme for classifying them into causal and non-causal miRNAs in HNSCC. We also discuss the possibility of using miRNAs as prognostic and diagnostic biomarkers for HNSCC, based on existing literature. Finally, we present available evidence that shows how altered expression of specific miRNAs can contribute to various “hallmarks of cancer” phenotypes such as limitless replicative potential owing to abnormal cell cycle regulation, evasion of apoptosis, reduced response to anti-growth signals, and Epithelial–Mesechymal transition (EMT).
Keywords: Head and neck squamous cell carcinoma; MicroRNA; Biomarker; Oral cancer
A miR-centric view of head and neck cancers
by Janki Mohan Babu; R. Prathibha; V.S. Jijith; Ramkumar Hariharan; M. Radhakrishna Pillai (pp. 67-72).
Head and Neck Squamous Cell Carcinomas (HNSCCs) constitute the sixth most common cancer worldwide with an average 5-year survival rate of around 50%. Several microRNAs, small non-coding RNAs involved in post-transcriptional gene regulation, have been linked to HNSCC based on their differential expression in tumors. Here, we present a compilation of multiple types of information on each HNSCC linked miRNA including their expression status in tumors, their molecular targets relevant to cancer, results of gene manipulation studies and association with clinical outcome. Further, we use this information to devise a new scheme for classifying them into causal and non-causal miRNAs in HNSCC. We also discuss the possibility of using miRNAs as prognostic and diagnostic biomarkers for HNSCC, based on existing literature. Finally, we present available evidence that shows how altered expression of specific miRNAs can contribute to various “hallmarks of cancer” phenotypes such as limitless replicative potential owing to abnormal cell cycle regulation, evasion of apoptosis, reduced response to anti-growth signals, and Epithelial–Mesechymal transition (EMT).
Keywords: Head and neck squamous cell carcinoma; MicroRNA; Biomarker; Oral cancer
Junctions gone bad: Claudins and loss of the barrier in cancer
by Kursad Turksen; Tammy-Claire Troy (pp. 73-79).
The tight junctions (TJs) of epithelia are responsible for regulating the “fence and gate” function of polarized epithelial cells. It is now well-established that dysregulation of these functions contributes to initiation and progression of cancer. Recently, it has become clear that the Claudins, members of a large family of 27 closely related transmembrane proteins, play a crucial role in formation, integrity and function of TJs, the epithelial permeability barrier and epithelial polarization. A growing body of data indicates that Claudin expression is altered in numerous epithelial cancers in a stage- and tumor-specific manner. While a single universal mechanism is still lacking, accumulating evidence supports a role for epigenetic regulation of Claudin expression in tumorgenesis, with concomitant alterations in barrier function. We review here new insights and challenges in understanding Claudin function in normal physiology and cancer.
Keywords: Claudin; Tight junction; Permeability barrier; Epithelia; Cancer
Junctions gone bad: Claudins and loss of the barrier in cancer
by Kursad Turksen; Tammy-Claire Troy (pp. 73-79).
The tight junctions (TJs) of epithelia are responsible for regulating the “fence and gate” function of polarized epithelial cells. It is now well-established that dysregulation of these functions contributes to initiation and progression of cancer. Recently, it has become clear that the Claudins, members of a large family of 27 closely related transmembrane proteins, play a crucial role in formation, integrity and function of TJs, the epithelial permeability barrier and epithelial polarization. A growing body of data indicates that Claudin expression is altered in numerous epithelial cancers in a stage- and tumor-specific manner. While a single universal mechanism is still lacking, accumulating evidence supports a role for epigenetic regulation of Claudin expression in tumorgenesis, with concomitant alterations in barrier function. We review here new insights and challenges in understanding Claudin function in normal physiology and cancer.
Keywords: Claudin; Tight junction; Permeability barrier; Epithelia; Cancer
SIRT3 and cancer: Tumor promoter or suppressor?
by Turki Y. Alhazzazi; Pachiyappan Kamarajan; Eric Verdin; Yvonne L. Kapila (pp. 80-88).
Sirtuins (SIRT1–7), the mammalian homologues of the Sir2 gene in yeast, have emerging roles in age-related diseases, such as cardiac hypertrophy, diabetes, obesity, and cancer. However, the role of several sirtuin family members, including SIRT1 and SIRT3, in cancer has been controversial. The aim of this review is to explore and discuss the seemingly dichotomous role of SIRT3 in cancer biology with particular emphasis on its potential role as a tumor promoter and tumor suppressor. This review will also discuss the potential role of SIRT3 as a novel therapeutic target to treat cancer.
Keywords: Abbreviations; NAD; +; Nicotinamide adenine dinucleotide; NAM; Nicotinamide; CR; Calorie Restriction; OSCC; Oral Squamous Cell CarcinomaSirtuin-3; SIRT3; Cancer; Tumor promoter; Tumor suppressor
SIRT3 and cancer: Tumor promoter or suppressor?
by Turki Y. Alhazzazi; Pachiyappan Kamarajan; Eric Verdin; Yvonne L. Kapila (pp. 80-88).
Sirtuins (SIRT1–7), the mammalian homologues of the Sir2 gene in yeast, have emerging roles in age-related diseases, such as cardiac hypertrophy, diabetes, obesity, and cancer. However, the role of several sirtuin family members, including SIRT1 and SIRT3, in cancer has been controversial. The aim of this review is to explore and discuss the seemingly dichotomous role of SIRT3 in cancer biology with particular emphasis on its potential role as a tumor promoter and tumor suppressor. This review will also discuss the potential role of SIRT3 as a novel therapeutic target to treat cancer.
Keywords: Abbreviations; NAD; +; Nicotinamide adenine dinucleotide; NAM; Nicotinamide; CR; Calorie Restriction; OSCC; Oral Squamous Cell CarcinomaSirtuin-3; SIRT3; Cancer; Tumor promoter; Tumor suppressor
|
|
Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases