Research progress on relationship between receptor tyrosine kinase-like orphan receptor 1 and signaling pathway of tumor cells
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摘要:
受体酪氨酸激酶样孤儿受体1(ROR1)属于受体酪氨酸激酶(RTKs)大家族的一种表面跨膜蛋白, 在调控骨骼与神经的发育, 细胞迁移与细胞极性中有重要作用。ROR1在正常组织中表达低或不表达, 在肿瘤组织中高表达。研究发现ROR1能与配体螯合来调节Wnt等多种细胞信号通路, 从而在多种疾病尤其是恶性肿瘤中发挥重要的作用, 逐渐成为恶性肿瘤的治疗靶标。本文就ROR1在恶性肿瘤中与细胞信号通路相互作用及靶向ROR1肿瘤免疫治疗的研究进展进行综述, 为肿瘤临床治疗策略的制订提供参考。
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关键词:
- 受体酪氨酸激酶样孤儿受体1 /
- 恶性肿瘤 /
- 细胞内信号通路 /
- 肿瘤免疫治疗
Abstract:Receptor tyrosine kinase-like orphan receptor 1 (ROR1) belongs to the transmembrane protein family of receptor tyrosine kinases (RTKs), and plays an important role in regulating the development of bones and nerves as well as cell migration and cell polarity. ROR1 is expressed at low or no levels in normal tissues, but is highly expressed in tumor tissues. Researches have found that ROR1 can regulate various cell signaling pathways such as Wnt through chelating with ligand, thereby playing an important role in multiple diseases, especially malignant tumors, and gradually become a therapeutic target for malignant tumors. This paper reviewed the interactions between ROR1 and cell signaling pathways in malignant tumors, the researches on targeted ROR1 tumor immunotherapy in order to provide references for clinical therapeutic strategies for tumors.
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结直肠癌是临床常见的恶性肿瘤之一，发病率呈逐年升高趋势。近年来，随着治疗方法的进步，结直肠癌患者的预后得以改善，但分期较晚、远处转移患者的预后仍不佳[1]。因此，探寻结直肠癌早期诊断与预后评估相关的分子标志物成为该研究领域的热点。Rictor蛋白是哺乳动物雷帕霉素靶蛋白复合物2(mTORC2)的成员，参与调控哺乳动物雷帕霉素靶蛋白(mTOR)信号通路。相关研究[2]表明, Rictor蛋白在结肠癌组织中高表达，与结肠癌的发生与发展有关。另有研究[3-4]提出，微小RNA-152(miR-152)和微小RNA-448(miR-448)可靶向调控Rictor蛋白而抑制结直肠癌细胞增殖。本研究观察Rictor蛋白在结直肠癌组织中的表达情况，并分析其与临床病理特征、预后的关系，现报告如下。
1. 资料与方法
1.1 一般资料
选取2014年6月—2018年6月在本院接受结直肠癌根治术治疗并经病理组织学检查确诊的90例结直肠癌患者作为研究对象。纳入标准: ①临床资料、病理数据无缺失者; ②经病理明确诊断结直肠癌者; ③术前未接受放化疗、免疫治疗等抗肿瘤治疗者; ④对本研究知情并签订书面同意书者。排除标准: ①存在其他器官恶性肿瘤者; ②怀孕期或哺乳期女性; ③近期接受过免疫抑制剂治疗，或存在严重感染者。90例患者中，男51例，女39例; 年龄44~78岁，平均(60.6±12.3)岁; 肿瘤部位为左侧结肠28例、右侧结肠31例、直肠31例; TNM分期为Ⅰ期30例、Ⅱ期40例、Ⅲ期20例; 肿瘤最大直径为1.5~5.5 cm, 平均(2.9±1.3) cm; 分化程度为低分化23例、中分化49例、高分化18例; 合并淋巴结转移30例; 浸润深度为T1期10例、T2期11例、T3期42例、T4期27例。收集90例患者的结直肠癌组织标本，并取对应的距癌组织5 cm处的正常结直肠组织作为对照，所有癌旁组织均经苏木素-伊红(HE)染色明确无癌细胞。
1.2 免疫组织化学方法
制备5 μm切片，实施脱蜡、脱水、水化等步骤，加入鼠抗人Rictor一抗(1 ∶ 50, 货号ab1203, 美国Sigma公司)，置于4 ℃冰箱过夜，用磷酸盐缓冲溶液(PBS)冲洗3次，加入兔抗鼠二抗(1 ∶ 100, 货号M282, 大连宝生物有限公司), 37 ℃孵育30 min, 用PBS冲洗3次，加入二氨基联苯胺(DAB)显色，封片，于光学显微镜下观察。半定量分析评分方法[2]: ①细胞质染色强度评分，无黄染为0分，淡黄色为1分，棕黄色为2分，黄褐色为3分; ②阳性细胞百分比≤5%为0分, >5%~25%为1分, >25%~50%为2分, >50%~75%为3分, >75%为4分。以①与②评分乘积表示Rictor蛋白表达水平，参照全部患者的平均分值(4.23分)，将 < 4.23分判定为低表达, ≥4.23分判定为高表达。
1.3 随访方法
对所有患者进行随访(门诊随访、电话随访等方式)，随访截止日期为2021年6月30日，随访时间为12~36个月，中位时间34个月，平均(34.1±8.0)个月，采用总体生存率对患者进行预后评价。
1.4 统计学分析
采用SPSS 20.0统计学软件分析数据, Rictor蛋白阳性表达情况、生存率等计数资料以[n(%)]、百分率(%)描述，比较行χ2检验。采用Kaplan-Meier法绘制结直肠癌组织Rictor蛋白低表达、高表达患者的生存曲线，采用Log-Rank检验对生存率进行比较，并采用单因素和多因素Cox回归分析探讨结直肠癌预后的影响因素。P < 0.05为差异有统计学意义。
2. 结果
2.1 Rictor蛋白在癌旁正常结直肠组织和结直肠癌组织中的表达情况
Rictor蛋白阳性表达细胞的染色表现为核周及细胞质内出现棕黄色或棕褐色颗粒。结直肠癌组织中Rictor蛋白阳性表达率为55.6%(50/90), 高于癌旁正常结直肠组织的11.1%(10/90), 差异有统计学意义(χ2=40.034, P < 0.001)。见图 1。
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图 1 Rictor蛋白在癌旁正常结直肠组织及结直肠癌组织中的表达(光学显微镜，放大200倍)A: Rictor蛋白在癌旁正常结直肠组织中阴性表达; B: Rictor蛋白在结直肠癌组织中阴性表达; C: Rictor蛋白在结直肠癌组织中阳性表达。2.2 结直肠癌组织中Rictor蛋白阳性表达与临床病理特征的关系
结直肠癌组织中Rictor蛋白阳性表达率与肿瘤最大直径、浸润深度、TNM分期、分化程度和淋巴结转移有关(P < 0.05), 与性别、年龄及肿瘤部位无关(P>0.05), 见表 1。
表 1 不同临床病理特征患者结直肠癌组织中Rictor蛋白阳性表达情况比较[n(%)]特征 分类 n Rictor蛋白阳性表达 χ2 P 性别 男 51 28(54.9) 0.523 0.462 女 39 22(56.4) 年龄 < 60岁 47 24(51.1) 0.682 0.402 ≥60岁 43 26(60.5) 肿瘤最大直径 < 3 cm 46 21(45.7) 6.521 0.014 ≥3 cm 44 29(65.9) 肿瘤部位 左侧结肠 28 14(50.0) 0.463 0.615 右侧结肠 31 19(61.3) 直肠 31 17(54.8) 浸润深度 T1~T2期 21 6(28.6) 11.623 < 0.001 T3~T4期 69 44(63.8) TNM分期 Ⅰ期 30 11(36.7) 9.727 < 0.001 Ⅱ期 40 24(60.0) Ⅲ期 20 15(75.0) 分化程度 低分化 23 19(82.6) 14.886 < 0.001 中分化 49 24(49.0) 高分化 18 7(38.9) 淋巴结转移 有 30 22(73.3) 8.734 < 0.001 无 60 28(46.7) 2.3 Rictor蛋白表达与结直肠癌患者预后的关系
本研究90例结直肠癌患者均未失访，结直肠癌组织Rictor蛋白低表达患者的总体生存率高于Rictor蛋白高表达患者，差异有统计学意义(P < 0.05), 见图 2。
2.4 结直肠癌患者预后的单因素、多因素Cox回归分析
将患者是否死亡作为因变量，将性别(男、女)、年龄(< 60岁、≥60岁)、肿瘤部位(右侧结肠、左侧结肠、直肠)、Rictor蛋白(低表达、高表达)、肿瘤最大直径(< 3 cm、≥3 cm)、浸润深度(T1~T2期、T3~T4期)、TNM分期(Ⅰ~Ⅱ期、Ⅲ期)、分化程度(高分化、低中分化)和淋巴结转移(有、无)作为自变量，进行单因素、多因素Cox回归分析。分析结果显示, Rictor蛋白高表达、TNM分期Ⅲ期是结直肠癌患者死亡的独立危险因素(P < 0.05), 见表 2。
表 2 结直肠癌患者预后的单因素、多因素Cox回归分析因素 单因素分析 多因素分析 HR 95%CI P HR 95%CI P Rictor蛋白 2.491 1.193~5.201 0.015 2.401 1.103~5.230 0.026 性别 0.894 0.491~1.635 0.718 — — — 年龄 1.174 0.626~2.202 0.618 — — — 肿瘤最大直径 2.766 1.512~5.061 0.001 0.888 0.323~2.441 0.818 肿瘤部位 0.962 0.751~1.234 0.761 — — — TNM分期 2.037 1.194~3.473 0.009 2.319 1.268~4.242 0.006 淋巴结转移 3.003 1.541~5.857 0.001 1.052 0.355~3.120 0.927 分化程度 2.001 1.426~2.811 0.001 1.939 0.839~4.478 0.121 浸润深度 2.189 1.014~4.727 0.046 1.072 0.470~2.448 0.868 3. 讨论
结直肠癌是一种异质性肿瘤，其机制目前尚未阐明。基因组学研究[5]发现，结直肠癌组织中众多基因呈差异性表达。尽管免疫靶向治疗等治疗手段可大大改善结直肠癌患者的预后，提升患者的生活质量，但目前临床尚未发现有效的分子靶点。大量研究[6-8]发现，肿瘤浸润深度、TNM分期、分化程度和淋巴结转移等临床病理特征与结直肠癌预后有关。因此，寻找与临床病理特征及预后有关的分子标志物对于结直肠癌的早期诊断和预后评估具有重要意义。
Rictor蛋白属于mTORC2的成员，在肿瘤增殖、迁移、侵袭和上皮间质转化(EMT)等过程中发挥着重要作用[9-11]。研究[12]发现, Rictor蛋白在子宫内膜癌组织中高表达，是患者预后的独立危险因素。此外, Rictor蛋白在多种消化道肿瘤组织中高表达，且与患者的预后有关[13-15]。本研究采用免疫组织化学方法检测结直肠癌组织中Rictor蛋白表达情况，发现Rictor蛋白在结直肠癌组织中高表达，与相关研究[16]结论基本一致。黄仕思等[17]研究发现，沉默Rictor表达可抑制肝癌细胞的恶性生物学行为及EMT过程。由此推测, Rictor可能通过促进EMT而增加肿瘤细胞的恶性生物学行为。
临床病理特征是反映肿瘤进展和预测肿瘤患者预后的可靠指标。本研究分析Rictor蛋白与结直肠癌患者临床病理特征的关系后发现, Rictor蛋白阳性表达率与肿瘤最大直径、浸润深度、TNM分期、分化程度和淋巴结转移有关，提示Rictor蛋白与结直肠癌恶性生物学行为有关。本研究结果显示, Rictor蛋白高表达患者的总体生存率低于Rictor蛋白低表达患者，且Rictor蛋白高表达是结直肠癌患者死亡的独立危险因素。由此提示, Rictor蛋白高表达可能与结直肠癌患者的低生存率有关，推测Rictor蛋白通过调控肿瘤细胞EMT促进细胞侵袭、转移等恶性生物学过程，进而影响患者的预后[18]。但Rictor蛋白对结直肠癌的影响有待细胞功能实验和动物实验证实，且其具体作用机制也有待探索。
综上所述, Rictor蛋白在结直肠癌组织中高表达，且Rictor蛋白表达情况与结直肠癌患者临床病理特征和预后有关，但Rictor蛋白通过何种通路发挥作用尚需进一步开展体内外实验加以明确。
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