Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth
Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth
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DOI：
10.1593/neo.04571
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发表时间：
2005-06-01
期刊：
影响因子：
4.8
通讯作者：
Friedrich, K
中科院分区：
文献类型：
--
作者：
Corvinus, FM;Orth, C;Friedrich, K
结直肠癌（CRC）是西方国家发病率和死亡率的主要原因。到目前为止，它的分子定义主要是通过改变Wnt途径。我们在这里首次表明，信号换能器和转录激活子STAT3的异常活动积极地促进了这种恶性肿瘤，因此是CRC的潜在治疗靶点。在结直肠癌样本的去分化癌细胞和浸润淋巴细胞中发现了丰富的组成性STAT3活性，但在非肿瘤性结肠上皮中则没有。来自恶性结直肠肿瘤的细胞系在培养中失去了持续的STAT3活性。然而，将结肠癌细胞植入裸鼠后，STAT3活性恢复，这表明肿瘤微环境中的细胞外刺激可能是STAT激活的触发因素。通过白细胞介素-6或组成型活性STAT3突变体触发CRC细胞中的STAT3活性，促进癌细胞增殖，而通过显性阴性突变体抑制STAT3则会损害il -6驱动的增殖。在crc来源的异种移植肿瘤中阻断STAT3的激活会减缓其发展，这表明STAT3对结直肠癌肿瘤的生长有贡献。
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.