Targeting autophagy in HCC treatment: exploiting the CD147 internalization pathway

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Chemotherapy resistance is a significant challenge in liver cancer treatment.
• The protein CD147 is implicated in chemoresistance, but its precise role is unclear.
• Understanding CD147's mechanism is crucial for developing effective therapies for hepatocellular carcinoma (HCC).

Purpose of the Study:

• To investigate the role of CD147 internalization in inducing cytoprotective autophagy.
• To elucidate the molecular mechanisms by which CD147 contributes to chemotherapy resistance in HCC.
• To evaluate the therapeutic potential of combining chemotherapy with autophagy inhibitors.

Main Methods:

• Bioinformatic analysis of GEO and TCGA databases to identify key molecules.
• In vitro and in vivo studies using overexpression/knockdown systems to analyze CD147 internalization and autophagy.
• Immunohistochemistry, immunofluorescence, and mass spectrometry to study CD147-G3BP1 interactions in clinical samples.
• Tumor xenograft mouse models to assess autophagy induction and combination therapy efficacy.

Main Results:

• CD147 internalization and interaction with G3BP1, followed by lysosomal transport, were observed upon cisplatin treatment.
• The CD147-G3BP1 complex inhibits mTOR, promoting autophagy and enhancing chemoresistance in hepatoma cells.
• Elevated CD147 internalization correlated with chemotherapy recurrence and stem cell maintenance in HCC patients.
• Combination therapy with cisplatin and hydroxychloroquine improved treatment efficacy in mice.

Conclusions:

• CD147 internalization and subsequent lysosomal translocation of the CD147-G3BP1 complex induce cytoprotective autophagy via mTOR suppression.
• This mechanism contributes to reduced chemotherapy sensitivity in HCC.
• Targeting CD147-mediated autophagy with inhibitors alongside chemotherapy offers a potential therapeutic strategy for HCC.