Pedersen Rasmus S, Hettich Annika, Thorlacius-Ussing Jeppe, Langholm Lasse L, Crespo-Bravo Marina, Chen Inna M, Hansen Carsten P, Johansen Julia S, Diab Hadi M H, Jorgensen Lars N, Karsdal Morten, Willumsen Nicholas
Nordic Bioscience A/S, 2730, Herlev, Denmark.
Department of Biomedical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
BMC Cancer. 2025 May 20;25(1):905. doi: 10.1186/s12885-025-14283-w.
The extracellular matrix (ECM) protein Beta-Ig H3 (βigH3, also known as transforming growth factor β induced protein (TGFBI)) is related to poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Proteolytic cleavage of βigH3 has been shown to result in release of the N-terminal fragment covering amino acid 1 to 137, but whether the degradation of βigH3 is associated to prognosis has yet to be determined. In this study we developed an ELISA targeting a collagenase generated fragment of βigH3 (cβigH3) in human serum to use the fragment as a biomarker reflecting degradation of βigH3. We demonstrated that the assay was specific to the cleaved fragment (cβigH3) and confirmed the generation of cβigH3 from degradation of fibroblast generated matrices. Moreover, higher levels of cβigH3 were released upon degradation of matrices produced by TGF-β stimulated pancreatic fibroblast compared to matrices produced by pancreatic fibroblast without TGF-β stimulation, indicating an association of the biomarker with degradation of fibrotic matrix. To evaluate the clinical relevance, we first measured cβigH3 in a cohort of 220 patients with different types of cancer with detectable levels for all 11 cancer types. We then measured the cβigH3 biomarker in pre-treatment serum from a cohort of 469 patients with locally advanced or metastatic PDAC and found that high levels of cβigH3 were associated with longer overall survival independently of age, disease stage, performance status, carbohydrate antigen 19-9 (CA19-9), and the tumor fibrosis biomarker PRO-C3 as compared to patients with high levels of cβigH3 (HR 0.78, 95% CI: 0.0.61-0.98, p = 0.04). In conclusion, cβigH3 reflects proteolytic degradation of βigH3 and shows potential as an independent prognostic biomarker for patients with advanced PDAC.
细胞外基质（ECM）蛋白β-免疫球蛋白H3（βigH3，也称为转化生长因子β诱导蛋白（TGFBI））与胰腺导管腺癌（PDAC）患者的不良预后相关。已显示βigH3的蛋白水解切割会导致释放覆盖氨基酸1至137的N端片段，但βigH3的降解是否与预后相关尚待确定。在本研究中，我们开发了一种酶联免疫吸附测定法（ELISA），用于检测人血清中胶原酶产生的βigH3片段（cβigH3），以将该片段用作反映βigH3降解的生物标志物。我们证明该测定法对切割片段（cβigH3）具有特异性，并证实了成纤维细胞产生的基质降解会生成cβigH3。此外，与未受TGF-β刺激的胰腺成纤维细胞产生的基质相比，TGF-β刺激的胰腺成纤维细胞产生的基质降解时会释放更高水平的cβigH3，表明该生物标志物与纤维化基质的降解有关。为了评估其临床相关性，我们首先在一组220例不同类型癌症患者中测量了cβigH3，这11种癌症类型的水平均可检测到。然后，我们在一组469例局部晚期或转移性PDAC患者的治疗前血清中测量了cβigH3生物标志物，发现与cβigH3水平高的患者相比，高水平的cβigH3与更长的总生存期相关，且独立于年龄、疾病分期、体能状态、糖类抗原19-9（CA19-9）和肿瘤纤维化生物标志物PRO-C3（风险比0.78，95%置信区间：0.61-0.98，p = 0.04）。总之，cβigH3反映了βigH3的蛋白水解降解，并显示出作为晚期PDAC患者独立预后生物标志物的潜力。
