Discovery, identification and mechanism of chemosensitivity-relate biomarker inter-α-trypsin inhibitor heavy chain 4 in metastatic colorectal cancer

Abstract

Predictive biomarkers of response to chemotherapy in patients with metastatic colorectal cancer (mCRC) are needed to better characterize tumors and enable more tailored therapies. Here we used serum proteomics to screen for chemotherapy predictive markers. We found that higher baseline serum inter-α-trypsin inhibitor Heavy Chain 4 (ITIH4) expression in newly diagnosed mCRC patients was associated with poorer response to standard first-line chemotherapy. In addition, the higher expression of ITIH4 in CRC tissue also suggested poorer prognosis mCRC patients. Moreover, the overexpression of ITIH4 could promote the proliferation of CRC cells and reduce the sensitivity of CRC cells to 5-fluorouracil (5-FU) by inhibiting apoptosis in vivo and vitro. Through RNA-seq combined with bioinformatics analysis, we speculated that ITIH4 may activate phosphatidyl 3-kinase-protein kinase B (PI3K-AKT) pathway to inhibit apoptosis, thereby reducing the sensitivity of CRC cells to 5-FU. In conclusion, our findings unveil that ITIH4 is associated with CRC resistance to 5-FU, and may serve as a potential predictive biomarker for the sensitivity of advanced CRC patients to standard first-line chemotherapy regimens, and also provide a potential therapeutic target to render 5-FU resistance in CRC patients.