Expression of LDH-C4 and CMKLR1 in Breast Cancer Tissues and Their Relationship with Clinicopathological Characteristics，Tumor Markers and Prognosis
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摘要:
目的 探讨乳腺癌组织中乳酸脱氢酶C4（lactate dehydrogenase C4，LDH-C4）、趋化因子受体1（chemokine-like receptor 1，CMKLR1）表达及其与临床病理特征、肿瘤标志物和预后的关系。 方法 选取2016年1月至2020年6月成都市双流区第一人民医院收治的150例乳腺癌患者进行前瞻性队列研究，均行乳腺癌根治术，术中采集癌组织及癌旁正常组织，采用免疫组化染色法检测LDH-C4、CMKLR1表达，比较不同组织LDH-C4、CMKLR1表达，分析癌组织LDH-C4、CMKLR1表达与乳腺癌患者病理特征、血清肿瘤标志物[癌胚抗原（carcinoembryonic antigen，CEA）、糖类抗原153（cancer antigen 153，CA153）]的关系，随访6～60个月，Kaplan-Meier法分析癌组织LDH-C4、CMKLR1表达与术后无进展生存预后的关系，分层Cox回归分析术后无进展生存预后的影响因素，并进行癌组织LDH-C4、CMKLR1表达与无进展生存预后的亚组分析。 结果 乳腺癌组织LDH-C4阳性表达率为53.33%，高于癌旁正常组织的26.67%，CMKLR1阳性表达率为41.33%，低于癌旁正常组织的89.33%，差异有统计学意义（χ2 = 22.218、76.083，均P < 0.05）；病理分期为Ⅱ～Ⅲ期、有淋巴结转移、CEA > 5.39 μg/L、CA153 > 26.57 U/mL的乳腺癌患者癌组织LDH-C4阳性表达高于病理分期为Ⅰ期、无淋巴结转移、CEA≤5.39 μg/L、CA153≤26.57 U/mL患者，CMKLR1阳性表达低于病理分期为Ⅰ期、无淋巴结转移、CEA≤5.39 μg/L、CA153≤26.57 U/mL患者，差异有统计学意义（P < 0.05）；随访6～60个月，发生肿瘤进展患者33例，Kaplan-Meier生存分析显示，LDH-C4阳性患者5年总体无进展生存率为65.85%，低于阴性表达患者的92.06%，CMKLR1阳性表达患者为91.67%，高于阴性表达患者的67.06%（Log-rank χ2 = 11.748、8.832，P < 0.05）；Cox回归分析显示，病理分期、淋巴结转移、CEA、CA153、LDH-C4表达是无进展生存预后的独立危险因素，CMKLR1表达是无进展生存预后的独立保护因素（P < 0.05）；分层Cox比例风险回归分析显示，在分别校正病理分期、淋巴结转移状态、CEA及CA153水平后，LDH-C4阳性仍为乳腺癌患者无进展生存预后的危险因素（HR = 3.082，95%CI：1.889～5.027，P < 0.05），而CMKLR1阳性则为乳腺癌患者无进展生存预后的保护因素（HR = 0.902，95%CI: 0.825～0.986，P < 0.05）。 结论 LDH-C4、CMKLR1表达与乳腺癌的病理分期、淋巴结转移及血清肿瘤标志物密切相关，可共同构成影响术后无进展生存预后的强大风险网络，可为临床评估预后及实现术后精准管理提供新的理论框架。 Abstract:Objective To investigate the expression of lactate dehydrogenase C4 （LDH-C4） and chemokine-like receptor 1 （CMKLR1） in breast cancer tissues and their relationship with clinical pathological characteristics, tumor markers and prognosis. Methods A prospective cohort study was conducted on 150 patients with breast cancer admitted to the First People’ s Hospital of Shuangliu District, Chengdu from January 2016 to June 2020. All patients underwent radical mastectomy and Cancer tissues and adjacent normal tissues were collected intraoperatively. Immunohistochemical staining was used to detect LDH-C4 and CMKLR1 expression. LDH-C4 and CMKLR1 expression in different tissues was compared, and the relationship between the expression of LDH-C4 and CMKLR1 in cancer tissues and the pathological characteristics, serum tumor markers [carcinoembryonic antigen （CEA）, cancer antigen 153 （CA153）] of breast cancer patients was analyzed. Follow-up was conducted for 6～60 months. Kaplan-Meier method analysis was performed to analyze the relationship between LDH-C4 and CMKLR1 expression and postoperative progression-free survival （PFS） prognosis. Stratified Cox regression analysis was used to identify factors influencing PFS prognosis, and subgroup analysis of LDH-C4 and CMKLR1 expression with PFS prognosis were performed. Results The positive expression rate of LDH-C4 in breast cancer tissue was 53.33%, significantly higher than the 26.67% in adjacent normal tissue, while the positive expression rate of CMKLR1 was 41.33%, significantly lower than the 89.33% in adjacent normal tissue （χ2 = 22.218, 76.083, all P < 0.05）. In patients with pathological stage II–III, lymph node metastasis, CEA > 5.39 μg/L, and CA153 > 26.57 U/mL, the positive expression of LDH-C4 was higher, and CMKLR1 positive expression was lower compared to patients with stage I disease, no lymph node metastasis, CEA ≤ 5.39 μg/L, and CA153 ≤ 26.57 U/mL （P < 0.05）. During the 6～60 month follow-up, 33 patients experienced tumor progression. Kaplan-Meier survival analysis showed that the 5-year overall progression-free survival rate in LDH-C4 positive patients was 65.85%, lower than the 92.06% in negative patients, while CMKLR1 positive patients had a rate of 91.67%, higher than the 67.06% in negative patients （Log-rank χ2 = 11.748, 8.832, P < 0.05）. Cox regression analysis showed that pathological stage, lymph node metastasis, CEA, CA153 and LDH-C4 expression were independent risk factors for PFS prognosis, while CMKLR1 expression was an independent protective factor （P < 0.05）. Stratified Cox proportional hazard regression analysis showed that after adjusting for pathological stage, lymph node metastasis status, CEA and CA153 levels, LDH-C4 positive positively ramained a risk factor for PFS in breast cancer patients （HR = 3.082, 95%CI: 1.889～5.027, P < 0.05）, while CMKLR1 positivity was a protective factor for PFS （HR = 0.902, 95%CI: 0.825～0.986, P < 0.05）. Conclusion The expression of LDH-C4 and CMKLR1 is closely associated with pathological stage, lymph node metastasis and serum tumor markers of breast cancer, Together, they constitute a powerful risk network affecting postoperative PFS prognosis and provide a novel theoretical framework for clinical prognostic assessment and precision management after surgery. -
Key words:
- Breast cancer /
- LDH-C4 /
- CMKLR1 /
- Clinicopathological Characteristics /
- Tumor markers /
- Prognosis
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图 1 免疫组化检测LDH-C4、CMKLR1在乳腺癌组织与癌旁组织中的表达（×200）
A：癌旁组织中的LDH-C4；B：癌组织中的LDH-C4；C：癌组织中的CMKLR1；D：癌旁组织中的CMKLR1。
Figure 1. Immunohistochemical detection of LDH-C4 and CMKLR1 expression in breast cancer tissues and adjacent non-cancerous tissues （×200）
图 2 LDH-C4与CMKLR1在乳腺癌组织和癌旁正常组织中的阳性表达率比较
Figure 2. Comparison of positive expression rates of LDH-C4 and CMKLR1 in breast cancer tissues and adjacent normal tissues
图 3 癌组织LDH-C4、CMKLR1表达与无进展生存预后的关系
A：LDH-C4表达与无进展生存预后的关系； B：CMKLR1表达与无进展生存预后的关系。
Figure 3. Relationship between LDH-C4 and CMKLR1 expression in cancer tissue and progression-free survival prognosis
表 1 癌组织LDH-C4、CMKLR1表达与乳腺癌患者病理特征、血清肿瘤标志物的关系[n（%）]
Table 1. Relationship between LDH-C4 and CMKLR1 expression of LDH-C4 and CMKLR1 in cancer tissues and the pathological characteristics and serum tumor markers of breast cancer patients[n（%）]
项目 n LDH-C4 CMKLR1 阳性 χ2 P 阳性 χ2 P 年龄（岁） 0.336 0.562 0.200 0.655 < 50 71 38（53.52） 28（39.44） ≥50 79 46（58.23） 34（43.04） 病理类型 0.732 0.392 0.381 0.537 非浸润性癌 49 25（51.02） 22（44.90） 浸润性癌 101 59（58.42） 40（39.60） 肿瘤最大径（cm） 0.497 0.481 0.284 0.594 ≤2 93 50（53.76） 40（43.01） > 2 57 34（59.65） 22（38.60） 病理分期 9.201 0.002* 13.528 < 0.001* Ⅰ期 70 30（42.86） 40（57.14） Ⅱ～Ⅲ期 80 54（67.50） 22（27.50） 组织分化程度 1.627 0.443 1.506 0.471 高分化 41 20（48.78） 20（48.78） 中分化 54 30（55.56） 22（40.74） 低分化 55 34（61.82） 20（36.36） 淋巴结转移 11.668 0.001* 8.550 0.003* 有 57 42（73.68） 15（26.32） 无 93 42（45.16） 47（50.54） 分子分型 0.875 0.832 0.919 0.821 Luminal A 32 16（50.00） 15（46.88） Luminal B 37 20（54.05） 15（40.54） Her-2阳性 44 26（59.09） 16（36.36） 三阴性 37 22（59.46） 16（43.24） CEA（μg/L） 13.890 < 0.001* 16.502 < 0.001* ≤5.39 72 29（40.28） 42（58.33） > 5.39 78 55（70.51） 20（25.64） CA153（U/mL） 8.131 0.004* 12.156 < 0.001* ≤26.57 69 30（43.48） 39（56.52） > 26.57 81 54（66.67） 23（28.40） *P < 0.05。 
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表 2 影响乳腺癌患者无进展生存预后的单因素及多因素分析
Table 2. Univariate and multivariate analysis of factors affecting progression-free survival in breast cancer patients
因素 单因素 多因素 HR 95%CI P HR 95%CI P 年龄（以≤50岁为参照） 1.489 0.984～2.253 0.094 / / / 病理类型（以非浸润性癌为参照） 1.102 0.892～1.362 0.078 / / / 肿瘤最大径（以直径≤2 cm为参照） 1.425 0.992～2.047 0.059 / / / 病理分期（以Ⅰ期为参照） Ⅱ期 2.313 1.403～3.814 < 0.001* 1.930 1.225～3.041 < 0.001* Ⅲ期 4.202 3.149～5.607 < 0.001* 3.548 2.579～4.882 < 0.001* 分化程度（以高分化为参照） 中分化 1.057 0.887～1.259 0.099 / / / 低分化 1.148 0.982～1.341 0.082 / / / 淋巴结转移（以无转移为参照） 3.708 2.011～6.837 < 0.001* 3.136 1.941～5.067 < 0.001* 分子分型（以Luminal A为参照） Luminal B 1.067 0.842～1.352 0.074 / / / Her-2阳性 0.902 0.794～1.025 0.080 / / / 三阴性 1.131 0.903～1.417 0.079 / / / CEA（以≤5.39 μg/L为参照） 2.916 2.114～4.022 < 0.001* 2.529 1.682～3.802 < 0.001* CA153（以≤26.57 U/mL为参照） 2.852 1.972～4.125 < 0.001* 2.295 1.541～3.419 < 0.001* LDH-C4（以阴性为参照） 3.555 2.149～5.882 < 0.001* 3.082 1.889～5.027 < 0.001* CMKLR1（以阴性为参照） 0.934 0.874～0.998 < 0.001* 0.902 0.825～0.986 < 0.001* “/”表示无数据；*P < 0.05。
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表 3 校正不同临床病理因素后LDH-C4与CMKLR1表达对无进展生存期的分层Cox回归分析
Table 3. Stratified Cox regression of LDH-C4 and CMKLR1 expression on progression-free survival after adjustment for different clinicopathological factors
协变量 β S.E. Waldχ2 HR 95%CI P 病理分期 LDH-C4（阳性 vs. 阴性） 0.786 0.186 17.853 2.194 1.492～3.225 < 0.001* CMKLR1（阳性 vs. 阴性） −0.164 0.032 26.266 0.849 0.798～0.904 < 0.001* 淋巴结转移 LDH-C4（阳性 vs. 阴性） 0.849 0.204 17.319 2.339 1.433～4.017 < 0.001* CMKLR1（阳性 vs. 阴性） −0.090 0.015 36.000 0.914 0.887～0.941 < 0.001* CEA LDH-C4（阳性 vs. 阴性） 0.603 0.199 9.177 1.828 1.225～2.714 < 0.001* CMKLR1（阳性 vs. 阴性） −0.124 0.056 4.905 0.883 0.792～0.984 < 0.001* CA153 LDH-C4（阳性 vs. 阴性） 0.604 0.171 12.476 1.830 1.309～2.557 < 0.001* CMKLR1（阳性 vs. 阴性） −0.146 0.036 16.446 0.864 0.805～0.927 < 0.001* *P < 0.05。
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