Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA.
University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
Genes (Basel). 2021 May 16;12(5):749. doi: 10.3390/genes12050749.
Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The high mortality of CRC is related to its ability to metastasize to distant organs. The kallikrein-related peptidase Kallikrein 6 (KLK6) is overexpressed in CRC and contributes to cancer cell invasion and metastasis. The goal of this study was to identify KLK6-associated markers for the CRC prognosis and treatment. Tumor Samples from the CRC patients with significantly elevated transcript levels were identified in the RNA-Seq data from Cancer Genome Atlas (TCGA) and their expression profiles were evaluated using Gene Ontology (GO), Phenotype and Reactome enrichment, and protein interaction methods. KLK6-high cases had a distinct spectrum of mutations in titin (), , , and genes. Differentially expressed genes (DEGs) found in the KLK6-overexpressing CRCs were associated with cell signaling, extracellular matrix organization, and cell communication regulatory pathways. The top KLK6-interaction partners were found to be the members of kallikrein family (KLK7, KLK8, KLK10), extracellular matrix associated proteins (keratins, integrins, small proline rich repeat, S100A families) and TGF-β, FOS, and Ser/Thr protein kinase signaling pathways. Expression of selected KLK6-associated genes was validated in a subset of paired normal and tumor CRC patient-derived organoid cultures. The performed analyses identified KLK6 itself and a set of genes, which are co-expressed with KLK6, as potential clinical biomarkers for the management of the CRC disease.
结直肠癌（CRC）仍然是全球癌症相关死亡的主要原因之一。CRC 死亡率高与其能够转移到远处器官有关。激肽释放酶相关肽酶 Kallikrein 6（KLK6）在 CRC 中过表达，有助于癌细胞侵袭和转移。本研究的目的是确定与 CRC 预后和治疗相关的 KLK6 相关标志物。在癌症基因组图谱（TCGA）的 RNA-Seq 数据中鉴定出转录水平显著升高的 CRC 患者的肿瘤样本，并使用基因本体论（GO）、表型和反应组富集以及蛋白质相互作用方法评估其表达谱。KLK6 高表达病例在 titin（）、、、和基因中具有明显不同的突变谱。在 KLK6 过表达的 CRC 中发现的差异表达基因（DEGs）与细胞信号转导、细胞外基质组织和细胞通讯调节途径有关。发现 KLK6 的主要相互作用伙伴是激肽释放酶家族（KLK7、KLK8、KLK10）、细胞外基质相关蛋白（角蛋白、整合素、小脯氨酸富含重复、S100A 家族）和 TGF-β、FOS 和丝氨酸/苏氨酸蛋白激酶信号通路的成员。在一组配对的正常和肿瘤 CRC 患者衍生类器官培养物中验证了选定的 KLK6 相关基因的表达。进行的分析确定了 KLK6 本身和一组与 KLK6 共表达的基因作为 CRC 疾病管理的潜在临床生物标志物。
