Showing posts with label bladder cancer. Show all posts
Showing posts with label bladder cancer. Show all posts

Friday, November 22, 2013

The Hedgehog, Ptch1, AND the Gli zinc-finger transcription factors

If there is an example where GENE INTERFERENCE could have a meaningful impact, it is in this pathway like a deluge of gene activations.  The impact could extend from Basal cell to bladder cancers to Gliomas!

"PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product, is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgheog binds PTCH1, smoothened is released and signals cell proliferation." wikipedia.

POLIZIO ET AL
 The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis in normal physiology, and its dysregulation is a common theme in cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo is a seven-transmembrane protein, which was only recently shown to function as a G protein–coupled receptor (GPCR) with specificity toward the heterotrimeric guanine nucleotide-binding protein Gi. In addition to activating Gi, Smo signals through its C-terminal tail to inhibit Suppressor of Fused, resulting in stabilization and activation of the Gli family of transcription factors, which execute a transcriptional response to so-called "canonical Hh signaling."

WHEN YOU TALK ABOUT ZINC-FINGER YOU KNOW YOU ARE TALKING ABOUT HISTONE MODULATION AND DIRECT DNA INTERACTION, ALL OCCURING MOSTLY THE EPIGENETIC ZONE MOSTLY!  THEREFORE THIS COULD EFFECT EVEN THE LEUKEMIAS!
THE CRBCM IS TAKING A CLOSER LOOK!

"Gli regulation by the opposing activities of Fused and Suppressor of Fused

Maximilien Murone1,2ET AL!
Hedgehog (Hh) proteins are secreted factors that control cell proliferation and cell-fate specification1. Hh signalling is mediated in vertebrates by the Gli zinc-finger transcription factors (Gli1, Gli2 and Gli3) and in Drosophila by the Gli homologue Cubitus interruptus"

OTHER GENES IMPLICATED!

PTCH1 gene
WNT3A
IRF6
GLI
TGF-beta
TrkC: Neurotropin -Receptor

AND THE DANCE OF GENES CONTINUE!

Wednesday, March 27, 2013

LOX Lysyl-Oxidase

This gene found in gastric and bladder cancer is prognostic.  Its amplification allows the cell to deal with austere conditions in Metastatic conditions.  It seems to be amplifying under the impetus of HIF (Hypoxia induced factor). Its amplification appears more reactive than driving the resulting dowstream reaction.It can affect the structure of laminin and collagen through its formation of Aldehyde.
It can push proliferation by acting as a co-factor at nuclear level.
It can affect AKT (Protein Kinase B).
Recently, a study in Sarcoma using a Doxorubicin isoform was set in motion. Expression of LOX should be included in the analysis since Hypoxia was a component of the treatment.
LOX would not be a principal target in a treatment strategy since it addresses mostly metastasis, it either an adjunct treatment, or will have a role in Maintenance therapy.

Tuesday, March 26, 2013

A few Genes on Bladder Cancer

MUC1:  Mucinous cancers are known to be dangerous because by the time they are diagnosed, the extent is a little more then first thought.  Mucin is used by cancer cells to hide from immune detection it is believed.  MUC1 interacts with GrB 2 which affects a multitudes of other genes and transcription factors.Through YES1, it interacts with JAK2.  Action through JAK2 may have been why Epogen was prohibited for use in the Curable cancer setting.  JAK2 sensitizes cancer to Epogen, and to other growth factors!
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AZPG1

"Original Article

Oncogene 29, 5146-5158 (16 September 2010) | doi:10.1038/onc.2010.258

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

B Kong, C W Michalski, X Hong, N Valkovskaya, S Rieder, I Abiatari, S Streit, M Erkan, I Esposito, H Friess and J Kleeff
Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-β (TGF-β) signaling leads to aggressive cancer progression. In this study, we identified zinc-α2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation."
It is associated with FAT/cahchexic losses in these patients
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TMPRSS2-ERG fusion
NKX3
c-MYC
PTEN
Favorable Gene hCAP-D3
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In Gastric Cancer
LOX
RASSF6
MR1
miRNA 107 (DICER1)
PDCD4
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In Colon Cancer

Annexin
S100A4
SERCA
GF15
BAX

Saturday, March 16, 2013

THE AURORA KINASES

ONCE AGAIN YOU SEE HOW THE CELL PLAYS, USING SIMPLE THINGS THAT GET COMPLICATED REALLY QUICKLY! 
Given our current understanding of the way they are suppressed by normal activity of P53, the aurora Kinase inhibitors should be used in cancers where P53  is clearly dys-regulated, and  probably in disease with positive Prostate Stem Cell Antigen.  This open the door to Sarcomas (chondrosarcoma being the most cited) and Pancreatic cancers  (as well as Bladder cancers). 

GADD45, a P53 dependent protein that inhibits Cdc2/Cyclin B1 could therefore be the best predictor of Aurora activity.
Quantification of CDCA8/Borealin, BIRC5/survivin, and INCENP may provide additional information on AURORA KINASE ACTIVITY.  Like the core Binding Factor, these 3 Molecules form  the Chromosomal Passenger Complex (CPC) which interact with POGZ, EVI5, and JTB.

Niehrs at al further define the role of GADD45 as "Gadd45 recruits nucleotide and/or base excision repair factors to gene-specific loci and acts as an adapter between repair factors and chromatin, thereby creating a nexus between epigenetics and DNA repair."  Therefore explaining how P53 induced arrest is followed by DNA repair through recruitment of GADD45.   When the cell is trying to repair itself with increase in GADD45, of course it wont want to die, therefore over-expression of GADD45 decrease the c-JUN, protecting therefore from TNF induced apoptosis.   GADD45 is not good theoretically when you use Cisplatin or radiation for that matter!

*POGZ explains Nuclear transposition of P53 effects as it impacts SP1, a transcription factor with inteaction of all major playors in the cell including E2F1, POU2F1.   YOU TARGET SP1 WITH WITH AFERIN FOR EXAMPLE, IT IS IMPOSSIBLE TO COME UP EMPTY HANDED.

*EVI5
"Identification of Rab11 as a small GTPase binding protein for the Evi5 oncogene"

Abstract

The Evi5 oncogene has recently been shown to regulate the stability and accumulation of critical G1 cell cycle factors including Emi1, an inhibitor of the anaphase-promoting complex/cyclosome, and cyclin A. Sequence analysis of the amino terminus of Evi5 reveals a Tre-2, Bub2, Cdc16 domain, which has been shown to be a binding partner and GTPase-activating protein domain for the Rab family of small Ras-like GTPases. Here we describe the identification of Evi5 as a candidate binding protein for Rab11, a GTPase that regulates intracellular transport and has specific roles in endosome recycling and cytokinesis. By yeast two-hybrid analysis, immunoprecipitation, and Biacore analysis, we demonstrate that Evi5 binds Rab11a and Rab11b in a GTP-dependent manner. However, Evi5 displays no activation of Rab11 GTPase activity in vitro. Evi5 colocalizes with Rab11 in vivo, and overexpression of Rab11 perturbs the localization of Evi5, redistributing it into Rab11-positive recycling endosomes. Interestingly, in vitro binding studies show that Rab11 effector proteins including FIP3 compete with Evi5 for binding to Rab11, suggesting a partitioning between Rab11–Evi5 and Rab11 effector complexes. Indeed, ablation of Evi5 by RNA interference causes a mislocalization of FIP3 at the abscission site during cytokinesis. These data demonstrate that Evi5 is a Rab11 binding protein and that Evi5 may cooperate with Rab11 to coordinate vesicular trafficking, cytokinesis, and cell cycle control independent of GTPase-activating protein function.
Keywords: cytokinesis, GTPase-activating protein, recycling endosome".
*JTB

JTB (gene)

From Wikipedia, the free encyclopedia
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Jumping translocation breakpoint
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols JTB; HJTB; HSPC222; PAR; hJT
External IDs OMIM604671 MGI1346082 HomoloGene4870 GeneCards: JTB Gene
RNA expression pattern
PBB GE JTB 210434 x at tn.png
PBB GE JTB 210927 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 10899 23922
Ensembl ENSG00000143543 ENSMUSG00000027937
UniProt O76095 O88824
RefSeq (mRNA) NM_006694 NM_206924
RefSeq (protein) NP_006685 NP_996807
Location (UCSC) Chr 1:
153.95 – 153.95 Mb
Chr 3:
90.23 – 90.24 Mb

PubMed search [1] [2]
Jumping translocation breakpoint protein (JTB)
Identifiers
Symbol JTB
Pfam PF05439
InterPro IPR008657
Protein JTB also known as the jumping translocation breakpoint protein or prostate androgen-regulated protein (PAR) is a protein that in humans is encoded by the JTB gene.[1][2]
The JTB family of proteins contains several jumping translocation breakpoint proteins or JTBs. Jumping translocation (JT) is an unbalanced translocation that comprises amplified chromosomal segments jumping to various telomeres. JTB has been found to fuse with the telomeric repeats of acceptor telomeres in a case of JT. Homo sapiens JTB (hJTB) encodes a transmembrane protein that is highly conserved among divergent eukaryotic species. JT results in a hJTB truncation, which potentially produces an hJTB product devoid of the transmembrane domain. hJTB is located in a gene-rich region at 1q21, called EDC (Epidermal Differentiation Complex).[1] JTB has also been implicated in prostatic carcinomas.[3]

KANOME ET AL SUGGESTED

"JTB-induced clustering of mitochondria around the nuclear periphery and swelling of each mitochondrion. In those mitochondria, membrane potential, as monitored with a JC-1 probe, was significantly reduced. Coinciding with these changes in mitochondria, JTB retarded the growth of the cells and conferred resistance to TGF-beta1-induced apoptosis. These activities were dependent on the N-terminal processing and induced by wild-type JTB but not by a mutant resistant to cleavage. These findings raised the possibility that aberration of JTB in structure or expression induced neoplastic changes in cells through dysfunction of mitochondria leading to deregulated cell growth and/or death."
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ONCE AGAIN YOU SEE HOW THE CELL PLAYS, USING SIMPLE THINGS THAT GET COMPLICATED REALLY QUICK!

Tuesday, March 5, 2013

Bladder cancer in 2012:
Prevalence 73.5 Thousand patients in the USA
Deaths 14.9 thousands died with this disease.
Only 15% of patients have localized disease
50% of patients who have muscle invasion will eventually progress, Median survival in Metastatic disease is 14 months.
Smoking is an established risk factor for Bladder cancer

When the Bladder Muscle is invaded, Giving 3 cycles of chemotherapy (MVAC) before surgery is standard of care and lead to a 77 months median survival Versus 46 months with surgery alone (SWOG 8710.) . But only 20% of people receive Neoadjuvant Chemotherapy.   Mostly because the disease affect the elderly who's perfomance is judged poor for the chemotherapy, because of renal failure which preclude use of Cisplatin, and related comorbidilties which would make chemotherapy hazardous.

Genes reported in Bladder cancer:

MRE11
RAD50
NBS1
ATM
_______________________________________________-----These 4 genes all involves a close pathway.   Under chemical effect there is breakage of double chains DNA in bladder cells  The DNA Break trigger stimulate ATM by phosphorylation or similar activation, MRE1-RAD50-NBS1 is a complex molecule which must allow repair of the breakage by exposing it through "histone remodeling".  Mutations here will hamper this sequence of Activity.  "Breakage of DNA" and HOP, P53 activation is not far.  This is why intact P53 or wild type marks an early cancer. and Mutation of P53 is more a sign of an advanced Bladder cancer.
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H2AX-during Histone remodeling H2Ax replace H2A and participate in the triggering of check point arrest and therefore a key point to the Histone complex activity which is to control DNA transcription.
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CSS (Calpain family) contain DeK1 and CysPc and other anchors/molecules (Now you are going closer to treating AML)
Resistance to Cisplatin: ERCC1
Bcl-2
Overexpression of HRAS (in early disease)
70% have Mutation in FGFR3
P53 and Rb more advanced disease
P21, and P16 are also bad prognosis predictors.

NMP22 may be identified in the Urine for early detection of superficial bladder cancer



Friday, February 15, 2013

RANDOM NEWS

*Data released from the CDC 's Office on Smoking and Health were rather sobering.   between 2010 and 2011, the prevalence of Smoking did not drop despite a 58% quitting attempt rate recorded. People just smoke a little less as the proportion of those who reported smoking less than 30 packs per year dropped. In the United states, 19% of the Adult population smoke despite all the warning. This lead to 443,000 or half a million deaths related to smoking related illnesses in the United States alone (latest Jama pg 539).  Of these, approximately 165,000 will die of lung cancer (37%).
Carcinogens in cigarettes, ability to detoxify oneself, and presence of Estrogen receptor Beta in the lung seems to contribute.  Amount, length,and nature  of smoking exposure are recognized variables and influence the type of cancer found.    exposure to Radon, Arsenic, Chromium and others such as Nickel have also been implicated.  Host variations include Cytochrome P450, Glutathione S transferase and DNA repair enzymatic system.  Deficiency of Vitamin A, C beta-carotene, fruit and vegetable consumption have all be recognized to be associated with lung cancer risks.

Kidney, bladder, uterine cervix, head and neck cancers have all been linked to smoking.

*Up to 75% of patients with Bladder Cancer who are of European descent may have rs2294008, making this a significant Biomarker to be understood and targeted.

* A device approved by the FDA can recognize existence of cancer cells at the Margins of surgery to help the surgeon delineate his surgical Margin.  The Margin Probe uses an eletromagnectic recognition system to identify a "signature" of malignancy to tell the presence of Malignant cells.  This device can tell 3 times better reportedly where the cancer tissue ends!

*OFF AGAIN, ON AGAIN, MULTIVITAMIN SUPPLEMENTATION IS GOOD FOR YOU TO REDUCE RISK OF CANCER PER THE PHYSICIAN HEALTH STUDY II DESPITE THE LACK OF SIGNIFICANT DIFFERENCE IN MORTALITY.  THE DIFFERENCE WAS IN NUMBER OF CANCERS.