2. Academic Validation
  3. A TGF-β-dominant chemo-resistant phenotype of hepatoblastoma associated with aflatoxin exposure in children

A TGF-β-dominant chemo-resistant phenotype of hepatoblastoma associated with aflatoxin exposure in children

  • Hepatology. 2023 Jul 17. doi: 10.1097/HEP.0000000000000534.
Xiao Xiang 1,  Yijie Hao 1,  Cheng Cheng 2,  Huanjing Hu 3,  Huadong Chen 4,  Jiehui Tan 5,  Yuanqi Wang 1,  Xiaofei Liu 2,  Bo Peng 1,  Junbin Liao 1,  Ji Wang 3,  Yubin Xie 3,  Juncheng Liu 4,  Shuling Chen 6,  Lixia Xu 3 7,  Wenxuan Xie 1,  Ruidong Xue 8,  Ming Kuang 1 3 9,  Zhe Xu 4,  Hong Jiang 4,  Sui Peng 2 3 10
Affiliations

Affiliations

  • 1 Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 2 Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 3 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 4 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
  • 5 Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
  • 6 Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
  • 7 Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
  • 8 Peking University First Hospital, Translational Cancer Research, Beijing 100034, China.
  • 9 Sun Yat-sen University Zhongshan School of Medicine, Guangzhou,510080, China.
  • 10 Clinical Trial Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
PMID: 37459556 DOI: 10.1097/HEP.0000000000000534
Abstract

Background aims: Hepatoblastoma (HB) is the most common liver Cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in HB patients. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need.

Approach results: We performed an integrative analysis including single-cell RNA Sequencing, whole-exome Sequencing, and bulk RNA Sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multi-color immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors (TFs). Among them, the S2A subtype, characterized by strong expression of progenitor (MYCN, MIXL1) and mesenchymal TFs (TWIST1, TBX5), was defined as a new chemo-resistant subtype. The S2A subtype showed increased transforming growth factor beta (TGF-β) cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-β of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes hepatoblastoma to upregulate TGF-β. Furthermore, Clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis.

Conclusions: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.

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