Biology Reference
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Recently it has been suggested that the biological outcome of BRMS1 might
relate to its subcellular localisation. Prominent cytoplasmic localisation has been
related to increased disease survival of melanoma patients, inversely related to pro-
liferation and Akt activation. Nuclear localisation was linked with enhanced inva-
sion (Slipicevic et al., 2012). It is difficult to conceptualise these findings except by
mobilising other invasion associated genes, but none has been nominated to date and
endorse the findings as a point of departure in the study of melanoma malignancy.
However, BRMS1 does influence growth factor receptor genes and tumour suppres-
sors but not in the direction of invasion promotion.
Amplified expression of MiRNA-146a is known to reduce invasive ability and
this occurs together with inhibition of EGFR, NF-κB signalling and suppression
of MTA2 tumour promoter expression (Li et al., 2010c). BRMS1 upregulated both
miRNA-146a and miRNA-146b in metastatic breast cancer cell lines. Transfection of
these miRNAs into the cell lines suppressed
in vitro
cell migration and inhibited lung
metastasis of cells introduced via the tail vein of athymic mice (Hurst et al., 2009a).
The transfected cell lines also showed downregulation of EGFR, another feature
these miRNAs share with BRMS1. Nonetheless, how this can conceivably selec-
tively suppress metastatic spread without affecting tumorigenesis is unclear. BRMS1
is silenced by promoter methylation. It is conceivable that methylation of the gene
might occur in the later phases of progression. This is not unheard of. EPB41L3,
which is regarded as a tumour suppressor, has been reported to undergo tumour
stage dependent methylation in NSCLC (Kikuchi et al., 2005). Now then Nagji et al.
(2010) showed that in NSCLC, BRMS1 methylation and silencing were related to
tumour stage. Further, it has now emerged that that miRNA-342 is capable of sup-
pressing the expression of DNMT1. MiRNA-342 was downregulated in colon cancer
tissues and cell lines, but when expression levels were restored a marked reduction
of the expression of DNMT1 occurred. Therefore one does need to know the scope
and identity of miRNAs that are modulated in consort with alterations in BRMS1.
It is now abundantly clear that BRMS1 functions in collaboration with other sup-
pressor genes and, as discussed, with miRNAs with suppressor function. It is pos-
sible that the expression of some of the co-factors might be dependent upon degree
of progression. It has been postulated that colonic and ovarian cancer progression
is accompanied by a stage dependent expression of many genes, including suppres-
sor genes producing cumulative effects leading to the manifestation of progression
(Sherbet and Patil, 2006). Induction of angiogenesis is an essential requirement
for metastasis to occur. BRMS1 is able to induce ING4 which has been shown to
suppress the formation of blood vessels and the suppression of endogenous ING4
increases growth of human umbilical vein endothelial cells (HUVEC). Further sup-
port for the co-operation of ING4 and BRMS comes from the demonstration that
repression of ING4 abrogates the suppression by BRMS1 of growth of HUVEC
cells, but ING4 overexpression inhibited suppression of angiogenesis by BRMS1. In
other words, the downstream ING4 target is a requisite for the suppressor function of
BRMS1 (Li and Li, 2010). As discussed earlier, ING is known to influence DGCR8,
which is involved in the early steps of miRNA biogenesis. ING1 affects DGCR8
expression. Induction of ING1 suppresses cell proliferation and suppression of
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