Persistent STAT3 Activation in Colon Cancer Is Associated with Enhanced Cell Proliferation and Tumor Growth

Abstract

Colorectal carcinoma (CRC) is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6-driven proliferation. Blockade of STAT3 activation in CRC-derived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth.

Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

“…It would be interesting to determine whether Myc is also regulated by Hpo signaling and plays a role in adult tissue regeneration in mammals. Finally, activation of Stat3 has been implicated in inflammation-associated colon cancers [41][42][43]. Our finding that the JAK/STAT pathway can activate dMyc raises an interesting possibility that Stat3 may also regulate Myc expression in colon cancer cells.…”

Signal Transducer and Activator of Transcription 3 - A Promising Target in Colitis-Associated Cancer

“…The expression of STAT3 in colon adenoma was shown in Figure 2. The activated level of STAT3 was remarkably elevated in patients of CAC; along with STAT3 phosphorylation actively induced the anti-apoptotic genes including Bcl2 and Bcl-xl that also correlated with the tumor invasion, metastasis, and worse prognosis in CAC (Corvinus et al, 2005;Kusaba et al, 2005;Kusaba et al, 2006;Lassmann et al, 2007). Due to the remarkable role played by the STAT3 signaling pathway in intestinal inflammation and CRC, the STAT3 pathway was suggested to be primary and specific targeting pathway in selective therapeutic approach to CAC (Atereya and Neurath, 2008).…”

“…The constitutive activation of STAT3 is frequently discovered in clinical samples from a wide range of human carcinoma and established human cancer cell lines, such as multiple myeloma, glioblastoma, colorectal and hepatocellular carcinoma (Buttner et al, 2002;Corvinus et al, 2005;Kusaba et al, 2005;CarlettFalcone et al, 1999). The expression of STAT3 in colon adenoma was shown in Figure 2.…”

Current overview of colitis-associated colorectal cancer

“…Also, IL-6 was shown to promote angiogenesis [35]. At the cellular level, the over-expression of IL-6 is associated with the inactivation of Stat3 and its deletion in epithelial cells in the colonic mucosa [36,37].…”