Biology Reference
In-Depth Information
mediated by miRNAs, it might be appropriate to digress and provide here a resumé
of mTOR signalling.
Activation of mTOR signalling involves the formation of two complexes, namely
mTORC1 and mTORC2. mTORC1 is a complex of mTOR with Raptor (regulatory-
associated protein of TOR) and other components GβL (MLST8), whereas mTORC2
is composed of mTOR, GβL MLST8 and Rictor. The PI3K/Akt activation leads to
the phosphorylation of mTOR, which then phosphorylates the downstream targets
p70S6K and 4EBP leading in turn to cell proliferation (Foster et al., 2010). Another
component of the mTORC complexes is Deptor. It is an inhibitor of mTOR. In the
absence of Deptor, active mTORC1 and mTORC2 kinases phosphorylate S6K1,
4EBP1 and SGK1 (a serine/threonine kinase) leading to the phosphorylation of
downstream targets resulting in promotion of cell proliferation and survival and inhi-
bition of autophagy (Efeyan and Sabatini, 2010). Compatibly, Deptor occurs at low
levels in cancers ( Figure 3.1 ).
miRNAs, Cell Proliferation and Apoptosis
The miRNA family Let-7 members have been extensively investigated for their bio-
logical function and the modes of regulation of their function. Let-7 is a tumour
suppressor which is frequently downregulated in cancer (Finoux and Chartrand,
2008). But Let-7 family are not across the board tumour suppressors. Let-7e has
been reported to be upregulated in synovial sarcomas. Furthermore, experimentally
downregulating Let-7e (and also of miRNA-99b) has resulted in the suppression
of cell proliferation. Arguably cell proliferation seems to be targeted by miRNAs.
They show demonstrable effects on c-myc, but their influence on the expression of
members of the apoptosis gene family is not clear. One would have liked to see if
the effects on c-myc are translated phenotypically via cell proliferation regulation
by gadd45, cyclins, cdc25A and other, or regulation of apoptosis through the func-
tion of anti-apoptosis Bcl-2 and Bcl-XL or pro-apoptosis genes Bax, Bad, Bak,
etc. Nonetheless, it would be evident from the discussion below that the influences
of miRNAs on some determinants of cell proliferation and apoptosis have been
addressed.
In C5 molecular subtype of high-grade serous ovarian cancer, marked changes
occur in the expression of N-myc, Lin-28B, Let-7 and HMGA2 (the high mobility
group A2). Characteristic amplification and overexpression of N-myc, and overex-
pression of its targets Lin-28B together with loss of Let-7 expression and amplifi-
cation and overexpression of HMGA2 protein frequently associated with tumour
invasion and progression have been encountered (Helland et  al., 2011). The expan-
sion of cell population can also result from the inhibition of apoptosis. MiRNA-21
which is highly expressed in certain tumours has been reported to be anti-apoptotic
(Carletti et  al., 2010; Chan et  al., 2005) as well as being able to actively induce
cell proliferation (Asangani et  al., 2008; Roldo et  al., 2006; Si et  al., 2007). It
appears to be associated with promotion of invasion being able to suppress rever-
sion-inducing-cysteine-rich protein with Kazal motifs (RECK) (Reis et  al., 2012).
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