Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China.
Department of General Surgery, Peking University Third Hospital, Beijing 100191, China.
Biomolecules. 2024 Feb 22;14(3):265. doi: 10.3390/biom14030265.
Low efficacy of treatments and chemoresistance are challenges in addressing refractory hepatocellular carcinoma (HCC). SPINK1, an oncogenic protein, is frequently overexpressed in many HCC cases. However, the impact of SPINK1 on HCC treatment resistance remains poorly understood. Here, we elucidate the functions of SPINK1 on HCC therapy resistance. Analysis of SPINK1 protein level reveals a correlation between elevated SPINK1 expression and unfavorable prognosis. Furthermore, intercellular variations in SPINK1 expression levels are observed. Subsequent examination of single cell RNA-sequencing data from two HCC cohorts further suggest that -high cells exhibit heightened activity in drug metabolic pathways compared to -low HCC cells. High expression is associated with reduced sensitivities to both chemotherapy drugs and targeted therapies. Moreover, spatial transcriptomics data indicate that elevated expression correlates with non-responsive phenotype during treatment with targeted therapy and immune checkpoint inhibitors. This is attributed to increased levels of drug metabolic regulators, especially and , in -high cells. Experimental evidence further demonstrates that overexpression induces the expression of and , consequently promoting chemoresistance to sorafenib and oxaliplatin. In summary, our study unveils the predictive role of SPINK1 on HCC treatment resistance, identifying it as a potential therapeutic target for refractory HCC.
治疗效果不佳和化疗耐药性是治疗难治性肝细胞癌（HCC）的挑战。丝氨酸蛋白酶抑制剂 Kazal 型 1（SPINK1）是一种致癌蛋白，在许多 HCC 病例中经常过表达。然而，SPINK1 对 HCC 治疗耐药性的影响仍知之甚少。在这里，我们阐明了 SPINK1 对 HCC 治疗耐药性的作用。SPINK1 蛋白水平的分析表明，升高的 SPINK1 表达与不利的预后相关。此外，还观察到细胞间 SPINK1 表达水平的变化。对来自两个 HCC 队列的单细胞 RNA 测序数据的进一步检查进一步表明，与低 HCC 细胞相比，-高细胞在药物代谢途径中表现出更高的活性。高 表达与对化疗药物和靶向治疗的敏感性降低相关。此外，空间转录组学数据表明，在接受靶向治疗和免疫检查点抑制剂治疗时，升高的表达与无应答表型相关。这归因于药物代谢调节剂水平的升高，特别是 -高细胞中的 和 。实验证据进一步表明，过表达诱导 和 的表达，从而促进索拉非尼和奥沙利铂的耐药性。总之，我们的研究揭示了 SPINK1 对 HCC 治疗耐药性的预测作用，将其鉴定为难治性 HCC 的潜在治疗靶点。
