2.The fact that IL-6 is now the target for therapy in multiple sclerosis
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Interleukin-6: a new therapeutic target in systemic sclerosis?
Open
Steven O'Reilly"3. and some believe IL-10 recruits fibroblasts
"New concepts of IL-10-induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis.
Sun L, Louie MC"==========================================
All these facts point to one and only one gene to watch, SOCS3 and therefore the involvement of the JAK-STAT pathways. Indeed all Myelofibrosis end up in fibrosis and therefore a focus on SOCS3 is more than warranted. SOCS3 is first know as an inhibitor of the JAK/STAT pathways.
wikipedia: "The expression of this gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma. The protein encoded by this gene can bind to JAK2 kinase, and inhibit the activity of JAK2 kinase."
SOCS3 is not only an enhancer of KRAS pathways in colon cancer by removing the pathway break (RasGAP), (it should be SOCS3 we should be watching!), but SOCKS3 through its activity with PTPN11, brings you the CEACAM-1 connection (which we follow as CEA in colon cancer) and beyond the CEACAM, SOCS3 brings Annexin-1 the road to fibrosis. Remember how Mucinous Gastric cancers end up producing so much fibrosis in the peritoneum that patient die of intestinal obstruction, it is we as Doctors do not monitor IL-6, IL-10, Interferon levels, SOCS3 activity, CEA, and Annexin-1 for that matter. We think PEG tube instead of blocking Annexin activities!
If you happen not to believe, you should read Wikipidia:
" Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence of juvenile myelomonocytic leukemias (JMML). Activating Shp2 mutations have also been detected in neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colorectal cancer.[7] These data suggests that Shp2 may be a proto-oncogene. However, it has been reported that PTPN11/Shp2 can act as either tumor promoter or suppressor.[8] In aged mouse model, hepatocyte-specific deletion of PTPN11/Shp2 promotes inflammatory signaling through the STAT3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and spontaneous development of tumors. Decreased PTPN11/Shp2 expression was detected in a subfraction of human hepatocellular carcinoma (HCC) specimens.[8] The bacterium Helicobacter pylori has been associated with gastric cancer, and this is thought to be mediated in part by the interaction of its virulence factor CagA with SHP2.[9] wikipedia
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why do you believe CEA is elevated in Gastric,colon or even Breast cancers! This pathway is indeed in effect!
Even GUO et al spoke about this in their observation focused on Caveolin in Fibrosis, but stumbled on SOCS3 (Their Caveolin was not far from SOCS3):
" Real-time PCR revealed that the expression of the mandarin fish Mx, IRF-1, SOCS1, and SOCS3 genes involved in the poly(I:C)-induced Jak-Stat signaling pathway was impaired by the mCav-1 scaffolding domain peptide (mSDP)."
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SOCS3 is a powerful gene
and at CRBCM we still believe that a gene that can induce Malformation, is powerful.
SOCS3/PTPN11 is a powerful association:
Missense mutations in the PTPN11 locus are associated with both Noonan syndrome and Leopard syndrome.
It has also been associated with Metachondromatosis.[4]wikipidia
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To muscle up both Leonard and Noonan syndromes ("il faut le faire" the french will tell you!) et le faire fort!(DO IT STRONGLY)
AND THEY MANAGE TO DO THIS THROUGH MITF!
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