Disease Information

General Information of the Disease (ID: DIS00538)

• Name: Liver cancer
• ICD: ICD-11: 2C12

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: L-glutamine amidohydrolase (GLS) [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.10]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Intrahepatic cholangiocarcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.33E-18; Fold-change: 5.84E-01; Z-score: 9.68E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SCK-R cells; Liver; Homo sapiens (Human); CVCL_M271
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The observed elevation in GLS1 expression, which is important in glutaminolysis, and intracellular glutamine and glutamate levels in SCK-R cells, revealed that glutaminolysis was associated with metabolic reprogramming represented by cisplatin resistance in SCK-R cells. Indeed, treatment with CB-839 led to reduced L1CAM, AXL, and ZEB2 expression. Combination treatment with DRB18 and CB-839 reduced SCK-R cell proliferation. Based on these results, we speculate that inhibiting glucose and glutamine metabolism re-sensitized SCK-R cells to cisplatin.

Key Molecule: Mal, T-cell differentiation protein 2 (MAL2) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.10]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• Cell Pathway Regulation: Alcoholic liver disease; Activation; hsa04936
• In Vitro Model: HuCCT1 cells; Bile duct; Homo sapiens (Human); CVCL_0324
• In Vitro Model: RBE cells; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: ScRNA-seq
• Experiment for Drug Resistance: CCK8 assay; Edu test assay
• Mechanism Description: Our research unequivocally underscores the critical role of MAL2 as an oncogenic promoter in ICC. Upon exposure to EGF, MAL2 exhibits its ability to retain EGFR on the cell surface, thwarting the endocytosis process. This action consecutively triggers the PI3K/AKT/SREBP-1 signaling cascade, inciting an increase in lipid deposition within ICC cells.

Key Molecule: Mal, T-cell differentiation protein 2 (MAL2) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.10]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• Cell Pathway Regulation: Alcoholic liver disease; Activation; hsa04936
• In Vitro Model: HUCCT1 transfected with sh-MAL2; Liver; Homo sapiens (Human); CVCL_0324
• In Vitro Model: HUCCT1 transfected with sh-NC; Liver; Homo sapiens (Human); CVCL_0324
• In Vitro Model: RBE cells transfected with sh-MAL2; Liver; Homo sapiens (Human); CVCL_4896
• In Vitro Model: RBE cells transfected with sh-NC; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: ScRNA-seq
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Our research unequivocally underscores the critical role of MAL2 as an oncogenic promoter in ICC. Upon exposure to EGF, MAL2 exhibits its ability to retain EGFR on the cell surface, thwarting the endocytosis process. This action consecutively triggers the PI3K/AKT/SREBP-1 signaling cascade, inciting an increase in lipid deposition within ICC cells.

Key Molecule: Mal, T-cell differentiation protein 2 (MAL2) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.10]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• Cell Pathway Regulation: Alcoholic liver disease; Activation; hsa04936
• In Vivo Model: 6-week-old BALB/c nude mice; 6-week-old BALB/c nude mice which were subcutaneously administered 1????106 transfected HUCCT1 cells ; liver orthotopic-implantation models, 3????106 HUCCT1 cells were injected into the liver; Mice
• Experiment for Molecule Alteration: ScRNA-seq
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our research unequivocally underscores the critical role of MAL2 as an oncogenic promoter in ICC. Upon exposure to EGF, MAL2 exhibits its ability to retain EGFR on the cell surface, thwarting the endocytosis process. This action consecutively triggers the PI3K/AKT/SREBP-1 signaling cascade, inciting an increase in lipid deposition within ICC cells.

References

• Ref 1: Regulation of glucose and glutamine metabolism to overcome cisplatin resistance in intrahepatic cholangiocarcinoma. BMB Rep. 2023 Nov;56(11):600-605.
• Ref 2: MAL2 reprograms lipid metabolism in intrahepatic cholangiocarcinoma via EGFR/SREBP-1 pathway based on single-cell RNA sequencing. Cell Death Dis. 2024 Jun 12;15(6):411.