JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression

Table 1 Cholangiocyte receptors associated with the JAK-STAT signaling pathways: alterations of expression during cholangiocarcinoma predisposition and development

Receptor type	Norma	Direction of alteration		References
		Cholangiocarcinoma predisposition	Cholangiocarcinoma development
Prolactin receptor	Low	Up	Up Up	[7,58,148]
IL-6 receptor/gp130	Present	Up	Up Up	[2,5]
ErbB-2	Low/Absent	Up	Up Up	[2,138-140]
c-Met	Present	Up	Up Up	[2,5]
Growth hormone receptor	Moderate	Up	?	[72]
Leptin receptor	Present	?	?	[85]

Table 2 Known components of JAK-STAT signaling for receptors expressed in cholangiocytes

Receptor type	JAK	STATs	Negative regulators of JAK-STAT signaling	References
Prolactin receptor	JAK2	STAT5 > STAT3 > STAT1	SOCS3, SOCS1, SOCS2, CIS	[47,48,51-53]
Growth hormone receptor	JAK2	STAT5 > STAT3 > STAT1	SOCS3, SOCS1, SOCS2, CIS	[70,71]
Leptin receptor	JAK2	STAT3 > STAT5, STAT6, STAT1	SOCS3	[74-79]
IL-6 receptor/gp130	JAK1, 2, Tyk2	STAT3 > STAT1	SOCS3	[15,18-20,101,102,110-112]
ErbB-2	No, JAK3, TYK2	STAT3 > STAT5, STAT6	SOCS3, SOCS1, SOCS4, SOCS5	[23,132-136,149,150]
c-Met	No	STAT3 > STAT5, STAT1	SOCS3	[115-122]

Table 3 Cholangiocarcinoma marker genes with promoter putative STAT responsible elements

Cholangiocarcinoma altered genes1	Direction of alteration1	Putative STAT responsible elements	Regulation by STAT	References
HGF	Up	STAT3	Up	[113,114]
VEGF	Up	STAT3	Up	[157]
COX-2	Up	STAT3, STAT5	Up	[158]
Cyclin D1	Up	STAT5	Up	[16,155]
p53	Down and up	STAT1	Up	[159]
p21waf1/cip1	Down	STAT1, STAT3, STAT5	Up	[155,160,161]
p27kip1	Down	STAT3	Up	[162]
Bcl-2	Up	STAT3	Up	[16]
Bcl-Xl	Up	STAT3, STAT5	Up	[155,163]
Mcl-1	Up	STAT3	Up	[111,112]
MUC1	Up	STAT3, STAT1	Up	[164]
MUC4	Up	STAT	Up	[165]

¹Altered genes and direction of changes of their expression are adopted from[2].

Table 4 Nuclear prolactin receptor expression in rat liver transplanted RS-1 cholangiocarcinoma cells and adjacent hepatocytes as compared with normal cells

	Nuclear PrlR-positive immunoreactivity (arbitrary units), medians (upper and lower quartiles)
	Normal cholangiocytes	RS-1 cholangiocarcinoma cells	Normal hepatocytes	Tumor adjacent hepatocytes
Males	47 (0; 104)	191b (119; 288)	40 (26; 90)	308b (227; 381)
Females	113 (47; 194)	408b (256; 555)	59 (41; 101)	415b (266; 581)

^bP < 0.001 as compared with correspondent intact group, Mann-Witney U-test.