Department of Molecular and Integrative Physiology.
Carcinogenesis. 2014 Apr;35(4):795-806. doi: 10.1093/carcin/bgt379. Epub 2013 Nov 21.
Prolactin (PRL) is a secretory cytokine produced by various tissues. Binding to the cognate PRL receptor (PRLR), it activates intracellular signaling via janus kinase (JAK), extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) proteins. PRL regulates diverse activities under normal and abnormal conditions, including malignancies. Previous clinical data suggest serum PRL levels are elevated in colorectal cancer (CRC) patients. In this study, we first determined the expression of PRL and PRLR in colon cancer tissue and cell lines. Higher levels of PRLR expression were observed in the cancer cells and cell lines compared with normal colonic epithelial cells. Incubation of colon cancer cells with PRL-induced JAK2, STAT3 and ERK1/2 phosphorylation and increased expression of Jagged 1, which is a Notch-1 receptor ligand. Notch signaling regulates CRC stem cell population. We observed increased accumulation of the cleaved/active form of Notch-1 receptor (Notch intracellular domain) and increased expression of Notch responsive genes HEY1, HES1 and stem cell marker genes DCLK1, LGR5, ALDH1 and CD44. Finally, inhibiting PRL induced JAK2-STAT3 and JAK2-ERK1/2 using AG490 and PD98059, respectively, leads to complete abrogation of Notch signaling, suggesting a role for this pathway in regulating CRC stem cells. Together, our results demonstrate that cytokine signaling induced by PRL is active in colorectal cancers and may provide a novel target for therapeutic intervention.
催乳素（PRL）是一种由各种组织分泌的细胞因子。它与同源催乳素受体（PRLR）结合，通过 Janus 激酶（JAK）、细胞外信号调节激酶（ERK）和信号转导和转录激活因子（STAT）蛋白激活细胞内信号转导。PRL 在正常和异常情况下调节多种活动，包括恶性肿瘤。先前的临床数据表明，结直肠癌（CRC）患者的血清 PRL 水平升高。在这项研究中，我们首先确定了 PRL 和 PRLR 在结肠癌组织和细胞系中的表达。与正常结肠上皮细胞相比，癌细胞和细胞系中观察到 PRLR 表达水平更高。用 PRL 孵育结肠癌细胞可诱导 JAK2、STAT3 和 ERK1/2 磷酸化，并增加 Notch-1 受体配体 Jagged 1 的表达。Notch 信号通路调节 CRC 干细胞群。我们观察到 Notch-1 受体（Notch 细胞内结构域）的裂解/活性形式和 Notch 反应基因 HEY1、HES1 以及干细胞标记基因 DCLK1、LGR5、ALDH1 和 CD44 的表达增加。最后，使用 AG490 和 PD98059 分别抑制 PRL 诱导的 JAK2-STAT3 和 JAK2-ERK1/2，可完全阻断 Notch 信号通路，表明该通路在调节 CRC 干细胞中起作用。总之，我们的结果表明，PRL 诱导的细胞因子信号在结直肠癌中是活跃的，可能为治疗干预提供新的靶点。
