Abstract
Background
Studies have demonstrated that Sorting nexin 7 (SNX7) functions as an anti-apoptotic protein in liver tissue and plays a crucial role in the survival of hepatocytes during early embryonic development. However, its diagnostic and prognostic value as well as the predictive value of chemotherapy and immunotherapy have not been reported in hepatocellular carcinoma (HCC).
Methods
SNX7 mRNA expression and its diagnostic efficacy were examined in GEO datasets, and the findings were further confirmed in TCGA, ICGC cohorts, and cell lines. The protein level of SNX7 was determined using CPTAC and HPA databases, and the results were validated through immunohistochemistry (IHC). Survival analyses were performed in TCGA and ICGC cohorts, and the results were subsequently validated via Kaplan–Meier Plotter. The response to chemotherapy and immunotherapy was predicted via GDSC dataset and TIDE algorithm, respectively. R packages were employed to explore the relationship between SNX7 expression and immune infiltration, m6A modification, as well as the functional enrichment of differentially expressed genes (DEGs).
Results
The expression of SNX7 at both mRNA and protein levels was significantly upregulated in HCC tissues. SNX7 exhibited superior diagnostic efficacy compared to AFP alone for HCC detection, and combining it with AFP improved the diagnostic accuracy for HCC. High SNX7 was associated with unfavorable outcomes, including poor overall survival, disease-specific survival, progression-free survival, and advanced pathological stage, in patients with HCC, and SNX7 was identified as an independent risk factor for HCC. Moreover, elevated SNX7 expression was positively correlated with increased sensitivity to various chemotherapy drugs, including sorafenib, while it was associated with resistance to immunotherapy in HCC patients. Correlation analysis revealed a relationship between SNX7 and multiple m6A-related genes and various immune cells. Finally, enrichment analysis demonstrated strong associations of SNX7 with critical biological processes, such as cell cycle regulation, cellular senescence, cell adhesion, DNA replication, and mismatch repair pathway in HCC.
Conclusions
Our study highlights the association of SNX7 with the immune microenvironment and its potential influence on HCC progression. SNX7 emerges as a promising novel biomarker for the diagnosis, prognosis, and prediction of response to chemotherapy and immunotherapy in patients with HCC.
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Introduction
Hepatocellular carcinoma (HCC) accounts for more than 90% of primary liver cancer cases and represents the main histological type of liver cancer [1]. It constitutes approximately 6% of all human cancers [2] and ranks second globally in terms of cancer-related mortality, posing a major challenge to public health. Despite significant advancements in research and clinical efforts, the prognosis for patients with advanced HCC remains unsatisfactory. Therefore, it is critically needed to identify new and reliable predictors for the clinical treatment and improvement of prognosis of patients with liver cancer.
Sorting nexin 7 (SNX7), an early endosome and multivesicular-body-distributed protein, is one of the members of the sorting nexin (SNX) family that plays vital roles in various intracellular biological processes, such as endocytosis, protein sorting, and endosomal signaling [3,4,5]. Previous research has demonstrated the importance of SNX7 in hepatocyte survival during early embryonic formation in zebrafish, where it functions as an anti-apoptotic protein abundant in liver tissue [64]. In our study, we found that HCC patients with low-expression SNX7 gaining a lower TIDE score exhibit a greater likelihood of responding to immune checkpoint blockade therapy. This suggests that SNX7 may have implications for predicting immunotherapy response in HCC patients.
In cancer, m6A modified genes usually play an oncogenic role [65], while m6A-related therapies, such as regulation or inhibition of m6A modifications may provide the potential therapeutic strategies for cancers [66]. We analyzed TCGA datasets and found that SNX7 expression was positively correlated with m6A modified genes. Moreover, these m6A modified genes were significantly elevated in the SNX7high HCC group. These results indicated that SNX7 may potentially have a role in predicting m6A-related therapies for treatment of HCC.
In this study, we have provided a systematic and comprehensive analysis of the potential role of SNX7 in HCC, however, there are some shortcomings that need to be considered. Firstly, although we have performed cross-validated using independent datasets, there could still be some bias in the selection of these datasets. Secondly, the exact molecular mechanism underlying the involvement of SNX7 in hepatocellular carcinoma remains unclear and requires further investigation in future studies. Third, although our results suggest that SNX7 may be a potential biomarker of response to chemotherapy and immunotherapy, additional clinical validation is necessary. These considerations should be considered when interpreting the results of our study.
Conclusion
Collectively, our findings suggest that SNX7 is abnormally elevated in HCC, associated with the immune microenvironment, and may affect the progression of HCC. SNX7 can be used as a promising novel biomarker for the diagnosis, prognosis, and prediction of response to chemotherapy and immunotherapy in HCC patients.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We are grateful to all the participants of the present study.
Funding
This study was supported in part by High-level Hospital Foster Grant of Fujian Provincial Hospital (Grant No. 2020HSJJ06) to Yi Huang, Medical Vertical Project of Fujian Province (Grant No. 2020CXB001) to Yi Huang, Natural Science Foundation of Fujian Province (Grant No. 2019J01176) to Yi Huang.
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Conceptualization, methodology, data curation, formal analysis, investigation, validation, writing original draft preparation: J Chen, G Gao; visualization, Y Zhang; review and editing: P Dai; supervision, project administration and funding acquisition:Y Huang. All authors have read and agreed to the published version of the manuscript.
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This study was sought and approved by the Ethics Committee of Fujian Provincial Hospital (Ethics Approval Number K2022-09–103). Informed consent was obtained from all subjects and/or their legal guardian(s). All methods were carried out in accordance with relevant guidelines and regulations.
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Chen, J., Gao, G., Zhang, Y. et al. Comprehensive analysis and validation of SNX7 as a novel biomarker for the diagnosis, prognosis, and prediction of chemotherapy and immunotherapy response in hepatocellular carcinoma. BMC Cancer 23, 899 (2023). https://doi.org/10.1186/s12885-023-11405-0
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DOI: https://doi.org/10.1186/s12885-023-11405-0