SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial Transcriptomics
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...
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MDPI AG
2024-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/3/265 |
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| author | Chunyuan Yang Limei Guo Juan Du Qiulu Zhang Lingfu Zhang |
| author_facet | Chunyuan Yang Limei Guo Juan Du Qiulu Zhang Lingfu Zhang |
| author_sort | Chunyuan Yang |
| collection | DOAJ |
| description | 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 <i>SPINK1</i>-high cells exhibit heightened activity in drug metabolic pathways compared to <i>SPINK1</i>-low HCC cells. High <i>SPINK1</i> expression is associated with reduced sensitivities to both chemotherapy drugs and targeted therapies. Moreover, spatial transcriptomics data indicate that elevated <i>SPINK1</i> 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 <i>CES2</i> and <i>CYP3A5</i>, in <i>SPINK1</i>-high cells. Experimental evidence further demonstrates that <i>SPINK1</i> overexpression induces the expression of <i>CES2</i> and <i>CYP3A5</i>, 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. |
| first_indexed | 2024-04-24T18:29:58Z |
| format | Article |
| id | doaj.art-45e37c86b1344592b5c748594e18e21e |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-04-24T18:29:58Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-45e37c86b1344592b5c748594e18e21e2024-03-27T13:27:49ZengMDPI AGBiomolecules2218-273X2024-02-0114326510.3390/biom14030265SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial TranscriptomicsChunyuan Yang0Limei Guo1Juan Du2Qiulu Zhang3Lingfu Zhang4Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, ChinaInstitute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, ChinaInstitute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, ChinaInstitute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, ChinaDepartment of General Surgery, Peking University Third Hospital, Beijing 100191, ChinaLow 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 <i>SPINK1</i>-high cells exhibit heightened activity in drug metabolic pathways compared to <i>SPINK1</i>-low HCC cells. High <i>SPINK1</i> expression is associated with reduced sensitivities to both chemotherapy drugs and targeted therapies. Moreover, spatial transcriptomics data indicate that elevated <i>SPINK1</i> 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 <i>CES2</i> and <i>CYP3A5</i>, in <i>SPINK1</i>-high cells. Experimental evidence further demonstrates that <i>SPINK1</i> overexpression induces the expression of <i>CES2</i> and <i>CYP3A5</i>, 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.https://www.mdpi.com/2218-273X/14/3/265SPINK1hepatocellular carcinomasingle cell RNA sequencingspatial transcriptomicsCES2CYP3A5 |
| spellingShingle | Chunyuan Yang Limei Guo Juan Du Qiulu Zhang Lingfu Zhang SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial Transcriptomics Biomolecules SPINK1 hepatocellular carcinoma single cell RNA sequencing spatial transcriptomics CES2 CYP3A5 |
| title | SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial Transcriptomics |
| title_full | SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial Transcriptomics |
| title_fullStr | SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial Transcriptomics |
| title_full_unstemmed | SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial Transcriptomics |
| title_short | SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial Transcriptomics |
| title_sort | spink1 overexpression correlates with hepatocellular carcinoma treatment resistance revealed by single cell rna sequencing and spatial transcriptomics |
| topic | SPINK1 hepatocellular carcinoma single cell RNA sequencing spatial transcriptomics CES2 CYP3A5 |
| url | https://www.mdpi.com/2218-273X/14/3/265 |
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