Kirana Chandra, Peng Lifeng, Miller Rose, Keating John P, Glenn Corinne, Shi Hongjun, Jordan T William, Maddern Guy J, Stubbs Richard S
1Discipline of Surgery, The Queen Elizabeth Hospital, Basil Hetzel Research Institute, University of Adelaide, 37a Woodville Road, Woodville, SA 5011 Australia.
2Wakefield Biomedical Research Unit, Wakefield Clinic, Wakefield Hospital, Wellington, New Zealand.
Clin Proteomics. 2019 Jan 22;16:3. doi: 10.1186/s12014-019-9223-7. eCollection 2019.
Biomarkers are urgently required to support current histological staging to provide additional accuracy in stratifying colorectal cancer (CRC) patients according to risk of spread to properly assign adjuvant chemotherapy after surgery. Chemotherapy is given to patients with stage III to reduce the risk of recurrence but is controversial in stage II patients. Up to 25% of stage II patients will relapse within 5 years after tumor removal and when this occurs cure is seldom possible. The aim of this study was to identify protein biomarkers to stratify risk of spread of CRC patients. Laser micro-dissection was used to isolate cancer cells from primary colorectal tumors of stage II patients which did or did not metastasize within 5 years after surgical resection. Protein expression differences between two groups of tumors were profiled by 2D-DIGE with saturation CyDye labeling and identified using MALDI-TOF mass spectrometry. Evaluation of protein candidates was conducted using tissue micro array (TMA) immunohistochemistry on 125 colorectal tumor tissue samples of different stages. A total of 55 differentially expressed proteins were identified. Ten protein biomarkers were chosen based on p value and ratio between non metastasized and metastazised groups and evaluated on 125 tissues using TMA immunohistochemistry. Expression of HLAB, protein 14-3-3β, LTBP3, ADAMTS2, JAG2 and NME2 on tumour cells was significantly associated with clinical parameters related to tumour progression, invasion and metastasis. Kaplan-Meier survival curve showed strong expression of six proteins was associated with good CRC specific survival. Expression of HLAB, ADAMTS2, LTBP3, JAG2 and NME2 on tumour cells, was associated with tumour progression and invasion, metastasis and CRC specific survival may serve as potential biomarkers to stratify CRC patients into low and high risk of tumour metastasis. Combined methods of laser microdissection, 2D DIGE with saturation labelling and MALDI-TOF MS proved to be resourceful techniques capable of identifying protein biomarkers to predict risk of spread of CRC to liver.
迫切需要生物标志物来辅助当前的组织学分期，以便在根据结直肠癌（CRC）患者的扩散风险进行分层时提供更高的准确性，从而在手术后合理分配辅助化疗。化疗用于III期患者以降低复发风险，但在II期患者中存在争议。高达25%的II期患者在肿瘤切除后5年内会复发，一旦复发，很少有治愈的可能。本研究的目的是鉴定蛋白质生物标志物，以分层CRC患者的扩散风险。使用激光显微切割技术从II期患者的原发性结直肠癌肿瘤中分离癌细胞，这些患者在手术切除后5年内发生或未发生转移。通过饱和CyDye标记的二维差异凝胶电泳（2D-DIGE）分析两组肿瘤之间的蛋白质表达差异，并使用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF）进行鉴定。使用组织微阵列（TMA）免疫组织化学对125个不同阶段的结直肠肿瘤组织样本进行蛋白质候选物评估。共鉴定出55种差异表达蛋白。根据非转移组和转移组之间的p值和比率选择了10种蛋白质生物标志物，并使用TMA免疫组织化学在125个组织上进行评估。肿瘤细胞上HLAB、蛋白质14-3-3β、LTBP3、ADAMTS2、JAG2和NME2的表达与肿瘤进展、侵袭和转移相关的临床参数显著相关。Kaplan-Meier生存曲线显示，六种蛋白质的强表达与良好的CRC特异性生存相关。肿瘤细胞上HLAB、ADAMTS2、LTBP3、JAG2和NME2的表达与肿瘤进展、侵袭、转移相关，CRC特异性生存可能作为潜在的生物标志物，将CRC患者分为低和高肿瘤转移风险组。激光显微切割、饱和标记的二维差异凝胶电泳和基质辅助激光解吸电离飞行时间质谱相结合的方法被证明是能够鉴定蛋白质生物标志物以预测CRC向肝脏扩散风险的有效技术。
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