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Updated: May 6, 2026
Targeted RNA Sequencing Assay to Characterize Gene Expression and Genomic Alterations
Published on: August 4, 2016
SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell
Chunyuan Yang1, Limei Guo1, Juan Du1
1Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China.
Abstract:
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 SPINK1-high cells exhibit heightened activity in drug metabolic pathways compared to SPINK1-low HCC cells. High SPINK1 expression is associated with reduced sensitivities to both chemotherapy drugs and targeted therapies. Moreover, spatial transcriptomics data indicate that elevated SPINK1 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 CES2 and CYP3A5, in SPINK1-high cells. Experimental evidence further demonstrates that SPINK1 overexpression induces the expression of CES2 and CYP3A5, 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.
Insights
Elevated SPINK1 protein levels predict poor outcomes in hepatocellular carcinoma (HCC) by increasing drug resistance. Targeting SPINK1 may overcome treatment challenges in refractory HCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Refractory hepatocellular carcinoma (HCC) presents significant treatment challenges due to low efficacy and chemoresistance.
- SPINK1, an oncogenic protein, is overexpressed in HCC, but its role in treatment resistance is not well understood.
Purpose of the Study:
- To investigate the functional impact of SPINK1 on HCC therapy resistance.
- To identify SPINK1 as a potential therapeutic target for refractory HCC.
Main Methods:
- Analysis of SPINK1 protein levels and correlation with prognosis.
- Examination of single-cell RNA-sequencing and spatial transcriptomics data from HCC cohorts.
- Experimental validation of SPINK1's role in chemoresistance.
Main Results:
- Elevated SPINK1 expression correlates with unfavorable prognosis and reduced sensitivity to chemotherapy and targeted therapies in HCC.
- SPINK1-high HCC cells show heightened drug metabolic pathway activity, particularly involving CES2 and CYP3A5.
- SPINK1 overexpression induces CES2 and CYP3A5, promoting resistance to sorafenib and oxaliplatin.
Conclusions:
- SPINK1 acts as a predictive biomarker for HCC treatment resistance.
- SPINK1 plays a crucial role in mediating chemoresistance through drug metabolic regulators.
- SPINK1 is a promising therapeutic target for overcoming treatment resistance in refractory HCC.
