Hepatocellular carcinoma represents the majority of primary liver cancers and makes up between 75% and 85% of all liver malignancies. This cancer shows aggressive behavior and quickly returns after treatment. The disease ranks among the top causes of cancer-related deaths globally.
The TBC1D family of proteins belongs to the TBC domain protein group which functions primarily to control cellular membrane transport and signal transmission through its role as Rab GTPase activating proteins (Rab GAPs). The various TBC1D family members play distinct roles in human hepatocellular carcinoma affecting tumor development as well as progression and metastasis while influencing drug resistance.
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TBC1D Family Members (TBC1Ds)
TBC1D family members (TBC1Ds) are a group of proteins containing Tre2-Bub2-Cdc16 (TBC) domains. TBC1Ds are unique in that they use a two-finger mechanism to inactivate their targets. In recent years, autophagy and glucose metabolism have been shown to play crucial roles in the pathogenesis and metastasis of HCC. In the early stages of cancer, especially during tumor development, autophagy disorders can often become a partial carcinogenic factor. However, autophagy can also promote cancer cell survival and chemoresistance during development. The role and speculated mechanism of TBC1D family members in HCC may be as follows:
| TBC1D Family |
Effects |
Mechanism |
Role in HCC |
| TBC1D3 |
Promote cancer |
EGFR/PI3K/AKT/mTOR signaling activation |
Promotes cell proliferation, resists apoptosis, and enhances glycolysis |
| TBC1D7 |
Suppress cancer |
Inhibition of mTORC1 |
Low expression is associated with poor prognosis of HCC |
| TBC1D15 |
May suppress cancer |
Rab7-mediated autophagy; mitochondrial dynamics |
May regulate HCC cell adaptability |
| TBC1D10A/B/C |
Promote cancer/promote metastasis |
Rab35-mediated cytoskeletal reorganization; EGFR endocytosis regulation |
Promotes HCC cell migration and invasion |
| TBC1D20 |
May promote cancer |
ER stress regulation; Rab1/Rab18-mediated membrane trafficking |
May affect HCC cell resistance |
TBC1D Transcription Levels in Hepatocellular Carcinoma Patients
Research findings indicated that six different TBC1D factors serve essential functions in autophagy. Researchers used the TIMER 2.0 database to examine TBC1D transcription levels across various cancer types. The mRNA of TBC1D shows strong upregulation in multiple cancer types such as colon cancer, bile duct cancer and pancreatic cancer when compared to normal samples. All six TBC1D members-TBC1D1, TBC1D7, TBC1D8, TBC1D9b, TBC1D14 and TBC1D25-displayed significant upregulation of mRNA levels in tissues of both hepatocellular carcinoma and cholangiocarcinoma. Analysis of the Gene Expression Omnibus database GSE102079 revealed higher TBC1D mRNA levels in HCC tissues than in surrounding tissues. Our additional examination of TBC1D mRNA levels using the UALCN database revealed that TBC1D1, TBC1D7, TBC1D8, TBC1D9b, TBC1D14, and TBC1D25 showed significantly higher expression in HCC tissues compared to normal liver tissues. All data demonstrate abnormal upregulation of TBC1Ds in HCC cases.
Fig. 1 Expression of TBC1Ds Protein in HCC (Zhang, P., et al. 2024).
TBC1D Genomic Variation in Hepatocellular Carcinoma
The TBC1D gene family produces proteins that manage vesicle transport, cell signaling and GTPase activity regulation while potentially impacting numerous cancer types. Hepatocellular carcinoma (HCC) reveals specific genomic variations within the TBC1D gene through different aspects.
TBC1D Gene Family Displays Associations with Liver Cancer Development
TBC1D family members including TBC1D1, TBC1D3, TBC1D7 and others function as key regulators of cell growth control and tumor formation through their involvement in metabolic pathways. TBC1D genes function as tumor suppressors or oncogenes which influence both the development and advancement of HCC.
TBC1D Gene Mutation Types
Point mutations (Single Nucleotide Variants, SNVs): These mutations can lead to missense mutations or nonsense mutations and cause splice site alterations that disrupt protein activity.
Copy Number Variations (CNVs): HCC tissues show amplification or deletion of TBC1D genes that result in altered expression levels.
Gene Fusions: Fusions of some TBC1D genes with other genes trigger abnormal signaling pathway activation.
Functional Impact of TBC1D Gene Mutations
Regulating AKT/mTOR Signaling Pathway
Some TBC1D family members including TBC1D7 associate with the TSC1/TSC2 complex to modulate mTORC1 signaling which controls liver cancer cell growth and metabolism.
Influencing Tumor Immune Microenvironment
Certain TBC1D gene mutations modify immune escape processes while impacting PD-L1 expression or the infiltration of T cells.
Promote or Inhibit Cell Proliferation and Migration
The TBC1D gene abnormalities influence RAB GTPases-mediated vesicle transport and thereby control the invasiveness of liver cancer cells.
Functions and Pathways of TBC1D Proteins and Gene Responses in Munich Cells
TBC1D3 and TBC1D10A/C and TBC1D20 function as tumor promoters which drive HCC progression by activating EGFR signaling pathways and changing cytoskeletal structure as well as inducing drug resistance.
TBC1D7 suppresses HCC cell proliferation through mTORC1 inhibition while TBC1D15 suppresses HCC cell survival through autophagy regulation.
The TBC1D family members influence liver cancer growth and metastasis, metabolism and drug resistance by utilizing the Rab GTPases signaling network which presents possible new precision treatment targets for HCC.
The TBC1D family members display complex functions within hepatocellular carcinoma by influencing tumor growth and metastasis as well as drug resistance through multiple Rab GTPases signaling pathways. Investigating TBC1Ds regulatory functions in HCC could reveal new precision treatment targets for liver cancer.
Reference
- Zhang, P., et al. A comprehensive analysis of the oncogenic and prognostic role of TBC1Ds in human hepatocellular carcinoma. PeerJ. 2024, 12: e17362.
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