The STAT protein regulates many cellular processes like growth, survival, and differentiation. When activated by chemical signals, STAT proteins move into the nucleus and regulate gene expression by binding to DNA. STAT3 specifically regulates genes involved in cell growth, division, movement, and apoptosis. It also helps control the immune response and is involved in bone formation. In hepatocellular carcinoma, STAT3 becomes constitutively active, promoting tumorigenesis by upregulating genes related to apoptosis, the cell cycle, angiogenesis, and metastasis. Evodiamine, a compound found in a plant, inhibits STAT3 activation and induces apoptosis in liver cancer cells by upregulating the phosphatase SHP-1, which dephosphorylates and de

2. The STAT protein :
(Signal Transducer and Activator of Transcription,
or Signal Transduction And transcription)
 regulates many aspects of growth, survival and
differentiation in cells

4.  STAT genes provide instructions for making proteins that are part of
essential chemical signaling pathways within cells.
 When STAT proteins are activated by certain chemical signals, they
move into the nucleus and attach (bind) to specific areas of DNA. By
binding to regulatory regions near genes,
 STAT proteins can regulate whether these genes are turned on or off.
 The STAT3 protein is involved in many cellular functions:
1. It regulates genes that are involved in cell growth
2. division,
3. cell movement,
4. and the self-destruction of cells (apoptosis).
 STAT3 In the immune system, the STAT3 protein transmits signals that
help control the body's response to foreign invaders such as bacteria
and fungi.
 the protein is involved in the regulation of inflammation, which is one
way the immune system responds to infection or injury.
 In the skeletal system, the STAT3 protein is involved in the formation
of specialized cells that build and break down bone tissue. These cells
are necessary for the normal development and maintenance of bones.

5.  Depending on the role of stat3 in cellular functions
as:
Regulation of genes that are involved in cell
growth and division,cell movement, and the self-
destruction of cells (apoptosis).
 STAT3 can promote oncogenesis by being
constitutively active through various pathways .
 STAT3 was shown to have an oncogenic or a
tumor suppressor role depending upon the
mutational background of the tumor.

8. -STAT3 activated by various cytokines and growth
factors like Interleukin-6 (IL-6) and Hepatocyte
growth factor(HGF).
-The ligation of these cytokines (IL-6 and IL-6
family cytokines) with their corresponding
receptors leads to the dimerization of
gp130(glycoproteins 130) followed by
dimerization of gp130 associated Janus kinases
(JAKs) and phosphorylation of JAKs and gp130.

9. -This receptor-kinase complex then recruits and
phosphorylates cytoplasmic protein STAT3.
Phosphorylated STAT3 forms a dimer and then
translocates into the nuclei and subsequently
induces transcription of many genes.
-Activated STAT3 also turns on strong negative
feedback loops involving SHP phosphatases
and suppressor of cytokine signaling3 (SOCS3).
These feedback mechanisms dampen STAT3
activity and ensure that cytokine-induced STAT3
activation is a transient event in normal cells.

11. In HCC STAT3 constitutively activated as
aresult of
-inflammation (Hepatitis)
-oxidative stress (accumulation of ROS)
-epigenetic silence of SOCS
-low expression levels of phosphatases

12. -activated STAT3 promotes tumorigenesis through
the upregulation of:
•antiapoptotic proteins (Bcl-xl and Bcl-2),
•cell cycle regulators (c-Mycand ,cyclinD).
Action of STAT3

13. -persistent activation of STAT3 also increases
angiogenesis and metastasis via upregulation of
vascular endothelial growth factor (VEGF),
hypoxia inducible factor 1 alpha (HIF1) and Basic
fibroblast
growth factor (BFGF), all of which are important
mediators of angiogenesis during tumor
formation.

16.  Evodiamine:-
 an alkaloid isolated from the dried, unripe fruit
of Evodia rutaecarpa.
 Evodiamine induced HCC apoptosis and
inhibited tumor growth.

17. Evodiamine suppressed :-
 interleukin-6 (IL-6)-induced activation of
STAT3 tyrosine 705 (Tyr705
) effectively.
 The phosphorylation of Janus-activated kinase
2 (JAK2), Src and extracellular regulated
protein kinases 1/2 (ERK1/2) were also
suppressed by evodiamine
 suppressed STAT3 DNA binding activity

18.  Evodiamine induced the expression of
phosphatase shatterproof 1 (SHP-1)
Which inhibit IL-6-induced STAT3 (Tyr705
)
activation.
 The inhibition of SHP-1 gene by small
interference RNA abolished the ability of
evodiamine to inhibit IL-6-induced STAT3
(Tyr705
) activation
In contrast

19. SHP-1 is a SH-2 containing tyrosine
phosphatase , which is :-
 kind of enzymes that dephosphorylates
tyrosine residues
protein tyrosine phosphatases

20. (SHP-1)
:-Is
tyrosine phosphatase
Which contain :-
SH-2
Which bind :-
Stat3
Leads to :-
Inhibition of STAT3 (Tyr705
) activation