Manufacture of novel RCAS1-targeting therapy against gynecologic cancer

RCAS1表达与各种癌症患者的总生存期显著相关。RCAS1在免疫细胞（如外周淋巴细胞和NK细胞）中分泌并诱导凋亡。为了阐明RCAS1的生物学意义，我们研究了1)RCAS1表达与肿瘤生长潜能的关系，以及2)RCAS1分泌的机制。1) siRNA敲低RCAS1表达可显著抑制SiSo和HOUA肿瘤细胞的体内生长。RCAS1表达增强可显著促进COS-7细胞源性肿瘤的体内生长。rcas1编码基因的引入增加了VEGF的表达。在子宫颈癌中，RCAS1表达与VEGF表达、微血管密度显著相关。2)子宫癌和卵巢癌患者血清RCAS1浓度明显高于健康献血者。RCAS1值也与治疗反应显著相关。WST-1检测显示患者血清诱导K562细胞生长抑制，但在RCAS1免疫缺失后，这种作用部分恢复。因此，RCAS1可能是妇科肿瘤的生物标志物。RCAS1是通过PKC-σ、Ras-MAPK和转激活途径通过外域脱落分泌的。获得与RCAS1生物学意义相关的分子机制数据，可能使我们探索针对妇科癌症的新疗法。

RCAS1 expression is significantly related to overall survival of patients with various cancers. RCAS1 is secreted and induces apoptosis in putative receptor expressing cells including immune cells such as peripheral lymphocytes and NK cells. To clarify the biological significance of RCAS1, we here investigated 1) the association between RCAS1 expression and tumor growth potential, and 2) mechanisms of RCAS1 secretion. 1) Knockdown of RCAS1 expression by siRNA significantly suppressed in vivo growth of SiSo and HOUA tumor cells. .Enhanced RCAS1 expression significantly promoted in vivo growth of tumors derived from COS-7 cells. Introduction of the RCAS1-encoding gene increased expression of VEGF. In uterine cervical cancer, RCAS1 expression was significantly 'associated with VEGF expression and microvessel density. 2) Uterine and ovarian cancer patients had significantly higher serum RCAS1 concentrations than did healthy blood donors. RCAS1 values were also significantly associated with response to treatment. The WST-1 assay showed that patients' serum induced K562 cell growth inhibition, but this effect partially recovered after immunodepletion of RCAS1. Therefore, RCAS1 may be a biomarker of gynecologic cancer. RCAS1 was secreted by ectodomain shedding via PKC-σ, Ras-MAPK, and transactivation pathways. Acquisition of data about the molecular mechanisms related to RCAS1 biological significance may allow us to explore novel therapies against gynecologic cancer.