Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany.
German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany.
Int J Mol Sci. 2021 Nov 16;22(22):12364. doi: 10.3390/ijms222212364.
p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statistical analyses of clinical data sets. p130Cas expression was associated with poor survival in the cancer genome atlas (TCGA) data set. Knockdown/reconstitution experiments showed that p130Cas drives migration but, unexpectedly, inhibits proliferation in CRC cells. TCGA data analyses identified the growth factor epiregulin (EREG) as inversely correlated with p130Cas. p130Cas knockdown and simultaneous EREG treatment further enhanced proliferation. RNA interference and EREG treatment experiments suggested that p130Cas/EREG limit each other's expression/activity. Inverse p130Cas/EREG Spearman correlations were prominent in right-sided and earlier stage CRC. p130Cas was inducible by 5-fluorouracil (5-FU) and FOLFIRI (folinic acid, 5-FU, irinotecan), and p130Cas and EREG were upregulated in distant metastases (GSE121418). Positive p130Cas/EREG correlations were observed in metastases, preferentially in post-treatment samples (especially pulmonary metastases). p130Cas knockdown sensitized CRC cells to FOLFIRI independent of EREG treatment. RNA sequencing and gene ontology analyses revealed that p130Cas is involved in cytochrome P450 drug metabolism and epithelial-mesenchymal transition. p130Cas expression was associated with poor survival in right-sided, stage I/II, MSS (microsatellite stable), or BRAF-mutated CRC. In summary, p130Cas represents a prognostic factor and potential therapeutic target in CRC.
p130Cas 与乳腺癌和肺癌的不良预后和治疗耐药性相关。为了阐明 p130Cas 在结直肠癌（CRC）进展/治疗耐药性中的功能和临床作用，我们进行了细胞培养实验和临床数据集的生物信息学/统计分析。p130Cas 表达与癌症基因组图谱（TCGA）数据集中的不良生存相关。敲低/重建实验表明，p130Cas 驱动 CRC 细胞迁移，但出乎意料的是，抑制增殖。TCGA 数据分析确定生长因子表皮调节素（EREG）与 p130Cas 呈负相关。p130Cas 敲低和同时 EREG 处理进一步增强了增殖。RNA 干扰和 EREG 处理实验表明，p130Cas/EREG 限制彼此的表达/活性。右侧和早期 CRC 中 p130Cas/EREG 的反向 Spearman 相关性显著。5-氟尿嘧啶（5-FU）和 FOLFIRI（亚叶酸、5-FU、伊立替康）诱导 p130Cas，p130Cas 和 EREG 在远处转移中上调（GSE121418）。在转移中观察到 p130Cas/EREG 的正相关性，在治疗后样本中更明显（尤其是肺转移）。p130Cas 敲低使 CRC 细胞对 FOLFIRI 敏感，而与 EREG 治疗无关。RNA 测序和基因本体分析表明，p130Cas 参与细胞色素 P450 药物代谢和上皮-间充质转化。p130Cas 表达与右侧、I/II 期、MSS（微卫星稳定）或 BRAF 突变的 CRC 的不良生存相关。总之，p130Cas 是 CRC 的预后因素和潜在治疗靶点。
