Nie Fang, Cao Jianguo, Tong Jinlu, Zhu Mingming, Gao Yuan, Ran Zhihua
Department of Intensive Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
J Biomed Sci. 2015 Jul 16;22(1):56. doi: 10.1186/s12929-015-0162-y.
Recently accumulated evidence suggests that Raf kinase inhibitor protein (RKIP) participates in regulation of many signaling pathways and plays an important role in tumorigenesis and tumor metastasis. However, studies investigating the role of RKIP in colorectal cancer have not been reported. The aim of this study was to investigate the role of RKIP on colorectal cancer cell differentiation, progression and its correlation with chemosensitivity.
Immunohistochemical analysis revealed that RKIP expression was higher in non-neoplastic colorectal tissue (NCRCT) and colorectal cancer tissue (CRCT) than that in metastatic lymph node tissue (MLNT) (P <0.05). P-ERK protein expression was higher in MLNT and CRCT than that in NCRCT (P = 0.02). Immunocytochemical analysis further revealed that RKIP expression was higher in the well differentiated cell line SW1116 as compared to that in the poorly differentiated cell line LoVo. Matrigel invasive assay demonstrated that the inhibition of RKIP by short hairpin RNA (shRNA) 271 transfection significantly increased the number of migrated cells (90.67 ± 4.04 vs. 37.33 ± 2.51, P <0.05), whereas over-expression of RKIP by PEBP-1 plasmid transfection significantly suppressed the number of migrated cells (79.24 ± 5.18 vs. 154.33 ± 7.25, P <0.05). Meanwhile, down-regulation of RKIP induced an increase in the cell survival rate by inhibiting apoptosis induced by hydroxycamptothecine.
RKIP was also found to be associated with cell differentiation, with a higher activity in well differentiated colorectal cancer cells than in poorly differentiated ones. The upregulated expression of RKIP in colorectal cancer cells inhibited cell invasion and metastasis, while downregulation of RKIP reduced chemosensitivity by inhibiting apoptosis induced by HCPT.
最近积累的证据表明，Raf激酶抑制蛋白（RKIP）参与多种信号通路的调控，在肿瘤发生和肿瘤转移中起重要作用。然而，关于RKIP在结直肠癌中作用的研究尚未见报道。本研究旨在探讨RKIP在结直肠癌细胞分化、进展中的作用及其与化疗敏感性的相关性。
免疫组织化学分析显示，RKIP在非肿瘤性结直肠组织（NCRCT）和结直肠癌组织（CRCT）中的表达高于转移性淋巴结组织（MLNT）（P <0.05）。P-ERK蛋白在MLNT和CRCT中的表达高于NCRCT（P = 0.02）。免疫细胞化学分析进一步显示，与低分化细胞系LoVo相比，高分化细胞系SW1116中RKIP的表达更高。基质胶侵袭试验表明，短发夹RNA（shRNA）271转染抑制RKIP可显著增加迁移细胞数量（90.67±4.04对37.33±2.51，P <0.05），而PEBP-1质粒转染过表达RKIP则显著抑制迁移细胞数量（79.24±5.18对154.33±7.25，P <0.05）。同时，RKIP的下调通过抑制羟基喜树碱诱导的凋亡导致细胞存活率增加。
还发现RKIP与细胞分化有关，在高分化结直肠癌细胞中的活性高于低分化细胞。结直肠癌细胞中RKIP表达上调抑制细胞侵袭和转移，而RKIP下调则通过抑制HCPT诱导的凋亡降低化疗敏感性。
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