JAK/STAT/SOCS‐signaling pathway and colon and rectal cancer

Abstract

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth. We evaluated the association between genetic variation in JAK1 (10 SNPs), JAK2 (9 SNPs), TYK2 (5 SNPs), SOCS1 (2 SNPs), SOCS2 (2 SNPs), STAT1 (16 SNPs), STAT2 (2 SNPs), STAT3 (6 SNPs), STAT4 (21 SNPs), STAT5A (2 SNPs), STAT5B (3 SNPs), STAT6 (4 SNPs) with risk of colorectal cancer. We used data from population-based case-control studies (colon cancer n=1555 cases, 1956 controls; rectal cancer n=754 cases, 959 controls). JAK2, SOCS2, STAT1, STAT3, STAT5A, STAT5B, and STAT6 were associated with colon cancer; STAT3, STAT4, STAT6, and TYK2 were associated with rectal cancer. Given the biological role of the JAK/STAT-signaling pathway and cytokines, we evaluated interaction with IFNG, TNF, and IL6; numerous statistically significant associations after adjustment for multiple comparisons were observed. The following statistically significant interactions were observed: TYK2 with aspirin/NSAID use; STAT1, STAT4, and TYK2 with estrogen status; and JAK2, STAT2, STAT4, STAT5A, STAT5B, and STAT6 with smoking status and colon cancer risk; JAK2, STAT6, and TYK2 with aspirin/NSAID use; JAK1 with estrogen status; STAT2 with cigarette smoking and rectal cancer. JAK2, SOCS1, STAT3, STAT5, and TYK2 were associated with colon cancer survival (HRR of 3.3 95% CI 2.01, 5.42 for high mutational load). JAK2, SOCS1, STAT1, STAT4, and TYK2 were associated with rectal cancer survival (HRR 2.80 95 %CI 1.63, 4.80). These data support the importance of the JAK/STAT-signaling pathway in colorectal cancer and suggest targets for intervention.

Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

“…STAT3 activation mechanism involves the phosphorylation of its tyrosine 705 residue followed by the formation of STAT3 dimer, which translocates to the nucleus and interacts with the promoter region of target genes (12). Several upstream kinases including Jak2 (16) and Src (17) have been reported to phosphorylate STAT3 at tyrosine705 residue. The decreased phosphorylation of STAT3, Jak2 and Src kinase by carnosol suggests that the apoptosis induction by this compound is mediated through inhibition of STAT3 signaling.…”

“…Several upstream kinases, such as Jak2 and Src, are known to phosphorylate STAT3 (16,17). We examined the effect of carnosol on the phosphorylation of Jak2 and Src kinase.…”

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

“…There are various cell growth signals transmitted through the RAS protein, such as those mediated by the HER family members, insulin‐like growth factor‐1 (IGF‐1), and FGF. Furthermore, cancer cells might be able to grow without the wild‐type RAS protein because of the expression of survival signals, such as those occurring via the AKT‐phosphatidylinositol‐3 kinase (PI3K) and Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways 35. ZOL is considered to have a strong antitumor effect because it inhibits not only the RAS protein but also mTOR‐mediated survival signals by inhibiting farnesylation of a RAS homolog enriched in the brain that activates mTOR 36…”

MicroRNA-155-5p in pathogenesis of cancer

“…Ин-тересно, что уровень продукции участников пути JAK / STAT / SOCS, контролируемых miR-155, часто используется в качестве прогностических маркеров при раке толстой и прямой кишки [49].…”