Immunoglobulin production by tumors

[Kofi]

The paper is about a year old, but the implications are absolutely
stunning. The recombination of genetic elements necessary for adaptive
immunity is deeply tied into the development of certain tumors. No
doubt this helps to explain tumor angiogenesis and innervation.

This might explain the carcinogenic/mutagenic properties of retinoids,
which cause FOXO1 retention in the nucleus and thus trigger RAG genes.

This establishes that the antigens to which we're exposed might have
profound effects not just epigenetically but also genetically.



Transcription factors E2A, FOXO1 and FOXP1 regulate recombination
activating gene expression in cancer cells.

Authors
Chen Z, et al. Show all
Chen Z, Xiao Y, Zhang J, Li J, Liu Y, Zhao Y, Ma C, Luo J, Qiu Y, Huang
G, Korteweg C, Gu J.

Journal

PLoS One. 2011;6(5):e20475. Epub 2011 May 31.

Affiliation

Department of Pathology, Shantou University Medical College, Shantou,
China.

Abstract

It has long been accepted that immunoglobulins (Igs) were produced by B
lymphoid cells only. Recently Igs have been found to be expressed in
various human cancer cells and promote tumor growth. Recombination
activating gene 1 (RAG1) and RAG2, which are essential enzymes for
initiating variable-diversity-joining segment recombination, have also
been found to be expressed in cancer cells. However, the mechanism of
RAG activation in these cancer cells has not been elucidated. Here, we
investigated the regulatory mechanism of RAG expression in four human
cancer cell lines by analyzing transcription factors that induce RAG
activation in B cells. By RT-PCR, Western blot and immunofluorescence,
we found that transcription factors E2A, FOXO1 and FOXP1 were expressed
and localized to the nuclei of these cancer cells. Over-expression of
E2A, FOXO1 or Foxp1 increased RAG expression, while RNA interference of
E2A, FOXO1 or FOXP1 decreased RAG expression in the cancer cells.
Chromatin immunoprecipitation experiments showed acetylation of RAG
enhancer (Erag) and E2A, FOXO1 or FOXP1 were bound to Erag in vivo.
These results indicate that in these cancer cells the transcription
factors E2A, FOXO1 and FOXP1 regulate RAG expression, which initiates Ig
gene rearrangement much in the way similar to B lymphocytes.


PMID
21655267


p-FOXO1 blocks diabetes development, inhibiting hepatic glucose
production; FoxO1(-/+)/Notch1(-/+) raises insulin sentivity in
diet-induced insulin resistance as does knockout of Notch
transcriptional effector Rbp-Jkappa; Notch1 gain-of-function promotes
insulin resistance in a FoxO1-dependent manner and induces
glucose-6-phosphatase (G6PH) expression; Notch inhibition by
gamma-secretase inhibitors raises insulin sensitivity after in vivo
administration in lean mice and in obese, insulin-resistant mice; Notch
inhibition may be beneficial in diabetes by offseting excessive
FoxO1-driven hepatic glucose production [PMID 21804540]

PI3K suppresses class-switch recombination in B cells; PTEN knockout in
B-cells exhibit a hyper-IgM condition due to impaired class-switch
recombination, which could be restored in vitro by specific inhibition
of PI3Kdelta; PI3K -> Akt -> FOXO inactivation -> suppressed
class-switch recombination, lower Ikaros, elevated IgM production [PMID
17000121]

IgM drives male-pattern baldness in women [PMID 22134564];

Foxo1 -> proper Ikaros mRNA splicing -> Ig class-switching (Ig gene
recombination) [PMID 22291095]; p-FOXO1 suppresses pre-B cell genes like
Rag1, Rag2 and BLNK [PMID 22267219]; mTORC2 -> PI3K/Akt -> p-FOXO1,
p-FOXO3a -> Ig recombination suppression in proliferating B cells to
block DNA breaks (& suppression of B-cell tumor development?) [PMID
21822797]