Inserm, U837, Lille F-59045, France.
Int J Oncol. 2010 Mar;36(3):689-98. doi: 10.3892/ijo_00000544.
REG4, the latest member of the regenerating gene family, is overexpressed in inflammatory bowel diseases and gastrointestinal carcinomas. To date, its pathophysiologic role has not been well established. Using HT-29 models, we previously identified REG4 as being overexpressed in colorectal tumor cells displaying a drug-resistance phenotype; some also displayed invasive properties. Thus, we investigated the potential functions of REG4 in biological processes involved in colorectal tumor progression such as cell proliferation, migration and invasion. Colon cancer cells secreting REG4 (HT29-5M21, HT29-5F7 and HT29/REG4-8) or not (HT-29, HT29/CT1 and Caco-2/TC7) were used to analyze the autocrine and paracrine effects of REG4. REG4 was continuously secreted into the culture medium of colon cancer cells. REG4 stimulated cell growth in a paracrine manner after 24 h of treatment. Notably, REG4 promoted migration and invasion of tumor cells in both an autocrine and paracrine manner, and these effects were significantly decreased by concomitant treatment with an anti-REG4 antibody. Using pharmacological inhibitors, we showed that PI3K/Akt, PKAs, PKCs and Rho-like GTPases, but not MAPK, are involved in REG4 invasion signals. In addition, REG4 expression was found to be increased in tissues harboring proliferation and migration properties such as the developing intestine and tissues from inflammatory bowel disease, hyperplastic polyps, adenoma and colorectal cancers. In various situations, REG4 expression was not confined to proliferating cells, regenerating cells or cells of the invasive front of metastatic tumors, suggesting that extracellular REG4 may act on epithelial cells in a paracrine manner. Altogether, our results indicate that REG4 is a multifunctional secreted protein which acts on colorectal cancer cells in an autocrine and paracrine manner. According to its biological functions and tissue expression, REG4 may play an important role in the development and progression of colorectal cancer, as well as in intestinal morphogenesis and epithelium restitution.
REG4 是再生基因家族的最新成员，在炎症性肠病和胃肠道癌中过度表达。迄今为止，其病理生理作用尚未得到很好的确定。我们之前使用 HT-29 模型发现，REG4 在表现出耐药表型的结直肠肿瘤细胞中过度表达，其中一些细胞还表现出侵袭特性。因此，我们研究了 REG4 在结直肠肿瘤进展中涉及的生物学过程中的潜在功能，如细胞增殖、迁移和侵袭。分泌 REG4 的结肠癌细胞（HT29-5M21、HT29-5F7 和 HT29/REG4-8）或不分泌 REG4 的细胞（HT-29、HT29/CT1 和 Caco-2/TC7）用于分析 REG4 的自分泌和旁分泌作用。REG4 持续分泌到结肠癌细胞的培养基中。REG4 在治疗 24 小时后以旁分泌方式刺激细胞生长。值得注意的是，REG4 以自分泌和旁分泌方式促进肿瘤细胞的迁移和侵袭，并且这些作用通过同时用抗 REG4 抗体处理而显著降低。使用药理抑制剂，我们表明 PI3K/Akt、PKAs、PKCs 和 Rho 样 GTPases，但不是 MAPK，参与 REG4 侵袭信号。此外，在具有增殖和迁移特性的组织中发现 REG4 表达增加，例如发育中的肠道和炎症性肠病、增生性息肉、腺瘤和结直肠癌的组织。在各种情况下，REG4 表达不仅限于增殖细胞、再生细胞或转移性肿瘤侵袭前沿的细胞，表明细胞外 REG4 可能以旁分泌方式作用于上皮细胞。总之，我们的结果表明，REG4 是一种多功能分泌蛋白，以自分泌和旁分泌方式作用于结直肠癌细胞。根据其生物学功能和组织表达，REG4 可能在结直肠癌的发展和进展中以及在肠道形态发生和上皮修复中发挥重要作用。
