肿瘤组织和胰腺癌血清中主要组织相容性复合体Ⅰ类相关链 A/B（MICA/B）的表达：尿酸积累在吉西他滨诱导 MICA/B 表达中的作用。

BACKGROUND

Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity.

METHODS

Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a 51Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC) and ELISA, respectively.

RESULTS

Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68%) pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil.

CONCLUSIONS

The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production.

背景

主要组织相容性复合体Ⅰ类相关链 A 和 B（MICA/B）是两种应激诱导配体，它们与免疫受体 NKG2D 结合，在介导 NK 和 T 细胞的细胞毒性方面发挥重要作用。在这项研究中，我们试图研究胰腺癌中的 MICA/B 表达，并确定是否以及如何遗传毒性药物（如吉西他滨）可以影响 MICA/B 表达和自然杀伤细胞的细胞毒性。

方法

通过流式细胞术分析 7 种胰腺癌细胞系的 MICA/B 表达，并通过 51Cr 释放测定分析其对 NK-92 细胞杀伤的敏感性。通过免疫组化染色（IHC）和 ELISA 分别分析肿瘤组织和胰腺癌患者血清中的 MICA/B 表达。

结果

两种 MICA/B 阳性细胞系对 NK-92 细胞的细胞毒性活性敏感。另外两种 MICA/B 阳性细胞系和三种 MICA/B 阴性细胞系对 NK-92 细胞杀伤具有抗性。MICA/B 表达在 25 例胰腺导管腺癌中的 17 例（68%）中为阳性，但在正常胰腺导管上皮细胞中未检测到。胰腺癌患者的血清 MICA/B 水平显著升高，但与胰腺癌的分期和患者的生存无关。吉西他滨治疗导致 10 例可检测到血清 MICA 的患者中有 6 例血清 MICA 水平升高。黄嘌呤氧化还原酶抑制剂别嘌呤醇可阻止黄嘌呤转化为尿酸，从而阻断尿酸产生、MICA/B 表达以及暴露于辐射和两种遗传毒性药物（吉西他滨和 5-氟尿嘧啶）的 PANC-1 癌细胞系对 NK-92 细胞杀伤的敏感性。