Roles of Oncogenes in Proliferation

Expression of c-Myc, c-Fos and c-Jun

in Hepatocellular Carcinoma
Yuen, et al. !!"
Presented #y$ %rigette Hales
Marc& "'t&, !!

Cell Cycle and Proliferation
(
Controlled and regulated #y se)eral
factors
(
Has a c&ec*point mec&anism to &alt
progress of cycle in case of$
+
failure to properly complete a stage
+
,-. or c&romosomal damage
(
Failure of sur)eillance system to detect
a#normalities cell deat& or
formation of cancer cell

Cell Cycle Continued///
(
Certain cell cycle in&i#itors present for
sur)eillance can also pre)ent uncontrolled
gro0t& of cancer cells/
(
Mutations of t&ese can gi)e rise to tumours/

-ormal Cell Cycle
R/ Hus*ey, "111

Cell Cycle C&ec*points
R/ Hus*ey, "111
p53 acts prior to ,-. replication #y detecting ,-.
damage and delaying entry into S until t&e damage
&as #een repaired/

2umour 3uppressor 4enes and
Oncogenes
(
234s encode proteins t&at restrain uncontrolled
cell gro0t& and pre)ent malignancy in cells
+
ex$ p53
(
Oncogenes encode proteins t&at promote loss of
cell cycle control, in&i#ition of apoptosis and
malignancy in cells
+
ex$ c-myc, c-fos and c-jun

5&ere do oncogenes come from6
(
Proto-oncogenes are genes in normal cells 0&ic&
encode proteins t&at &a)e normal function in cells
(
Proto-oncogenes Oncogenes )ia$
+
mutations causing altered properties of t&e proto-
oncogene product, in&i#iting its normal acti)ity
+
mutation of regulatory se7uences leading to
o)erexpression of t&e proto-oncogene
+
incorporation of foreign ,-. causing altered expression
or altered proto-oncogene product
+
some may arise from c&romosomal translocations

2ypes of Oncogenes
(
Four categories #ased on t&eir gene
products$
+
gro0t& factors or t&eir receptors
+
cytoplasmic protein *inases
+
nuclear transcription factors 8ex$ c-myc9
+
products t&at regulate apoptosis 8#loc*:induce9

Role of p53
(
Encodes a transcription factor t&at acti)ates
expression of genes in)ol)ed in cell cycle control
(
Regulatory roles include ,-. damage control,
cell cycle arrest 84" c&ec*point9 and induction of
apoptosis
(
0ild type p53 can #e induced #y c-myc
(
p53 acti)ity can #e repressed in cancer cells )ia$
+
excessi)e met&ylation of t&e p53 promoter
+
inacti)ation of protein product #y in&i#itory protein
M,M

Re7uirements for .ltered Cell 4ro0t&
(
Oncogenes act dominantly, needing only one
gene copy to generate t&e altered p&enotype
(
;oss of cell gro0t& control t&erefore re7uires$
+
mutations in #ot& copies of tumour-suppressor genes
+
mutation of one copy of t&e proto-oncogene

.l#erts, et al/ "11'

Expression of c-Myc, c-Fos and c-
Jun in Hepatocellular Carcinoma
(
O#<ecti)es$
+
2o e)aluate t&e expression of t&ese oncogenes
in patients 0it& Hepatocellular Carcinoma
8HCC9/
+
2o elucidate t&e mec&anism of &epato-
carcinogenesis 0it& regard to t&e expression of
t&ese oncogenes/

5&at are t&ey6
(
c-myc, c-fos and c-jun$
+
oncogenes 0&ic& encode transcription factors/
+
myc encodes a ,-.-#inding protein
+
fos and jun eac& encode a component of t&e
transcription factor .P"
(
c-fos re7uired for 7uiescent cells to enter cell cycle
(
c-jun is also in)ol)ed in apoptosis
+
o)erexpression due to mutation leads to
unregulated cell proliferation and cell
malignancy

Materials and Met&ods$
(
=mmuno&istoc&emical staining of tumour and
ad<acent non-tumour tissues using
monoclonal primary anti#odies against gene
products of c-myc, c-fos and c-jun/
(
Bcl-2 also traced using immunofluorescent
anti#odies
(
3imilar anti#odies used for detection of
mutated p53
(
also used anti#odies for detection of ot&er
p&enotypic mar*ers

=mmuno&istoc&emical staining of
HCC tissue samples
.9 Expression of c-myc
%9 Expression of c-fos
C9 Expression of c-jun

Results

Results
(
-egati)e association #et0een expression of
c-myc and mutated 8i/e/$ mar*ed9 p53
(
expression of c-myc in tumour tissue 0as
in)ersely proportional to t&e grade of
differentiation of t&e HCC samples
(
no association #et0een expression of c-myc
and bcl-2

,iscussion of c-myc results
(
Hig&er le)els of expression in ad<acent non-
tumour cells indicates RELATIVEL decreased c-
myc in tumour cells/
(
c-myc may ser)e as a c&ec*point in cellular
proliferation 8as is p539
(
do0n-regulation of c-myc may t&erefore cause
dysfunction of t&e c&ec*point
(
decreased c-myc expression 0as accompanied #y
an increase in mutant p53 expression <eopardi>ing
apoptosis of altered cells

,iscussion continued///
(
Reduced expression of c-myc is seconda!y to
t&e poor differentiation of tumour cells, rat&er
t&an caus"n# t&eir poorly differentiated
p&enotype/
(
-o role is played #y c-myc in triggering t&e .P"
pat&0ay in tumour cell proliferation 8i/e/$ no
correlation #et0een c-myc and c-fos$c-jun9

Results
(
-o association found #et0een t&e expression
of c-fos$c-jun and p53 or bcl-2
(
c-fos expression is greater in HCC tissue
compared 0it& non-tumour tissue
(
c-jun expression is &ig& in #ot& types of
tissue
(
possi#le coordinated expression of c-fos and
c-jun in HCC tissue/

,iscussion of c-fos and c-jun results
(
Possi#ility of coordinated expression of t&ese
t0o oncogenes in tumour tissue may reflect
coordinated tumour cell progression and cell
proliferation
(
may #e responsi#le for rapid tumour gro0t&$ a
c&aracteristic of HCC cells
(
exact significance of coordinated expression
remains to #e determined

Future ,irections
(
Confirmation of coordinated )ersus
uncoordinated expression of c-fos and c-jun
(
determine 0&at triggers expression of c-myc,
c-fos and c-jun oncogenes
(
determine functional role of t&eir gene
products in t&e progression of &epato-
carcinogenesis

ANY QUESTIONS?
EMAIL: 8bh2@qlink.queensu.ca