ADCY7 dictates N-cadherin stability to inhibit HCC metastasis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, remains a therapeutic challenge because of its propensity for early recurrence and metastasis. Our previous study has identified adenylate cyclase 7 (ADCY7), a member of the adenylate cyclase family, as a tumor suppressor in HCC through T cell-dependent immunity. Nevertheless, the exact role and underlying mechanisms of ADCY7 in HCC metastasis remain largely unknown.

METHODS

Immunohistochemistry was used to measure the expression levels of ADCY7 in HCC and its clinical relevance (n = 142). Transwell assay was conducted to examine cell migration and invasion. Tail-vein lung metastasis HCC model was utilized for in vivo experiments. Furthermore, the role of ADCY7 in regulating N-cadherin levels was investigated via quantitative PCR, Western blot, immunofluorescence, and co-immunoprecipitation.

RESULTS

Our results demonstrated that ADCY7 functioned as a critical suppressor of HCC metastasis. Clinically, reduced ADCY7 expression correlated with metastatic progression and poor prognosis (p = 0.02) in patients with HCC. Functional studies showed that ADCY7 re-expression potently inhibited HCC cell migration (p <0.0001) and invasion (p <0.0001) in vitro and attenuated pulmonary metastasis (p <0.05) in vivo. Mechanistically, ADCY7 served as a molecular scaffold to enhance the interaction between N-cadherin and the E3 ubiquitin ligase SMURF2 (SMAD Specific E3 Ubiquitin Protein Ligase 2), facilitating N-cadherin's K48 linked polyubiquitination at lysine 896 (K896) and promoting its degradation through proteasomal and lysosomal pathways. Importantly, exosomes harboring ADCY7 could be internalized by other HCC cells, suppressing N-cadherin expression and thus reducing metastatic burden.

CONCLUSIONS

Collectively, our findings unveil ADCY7 as a metastasis suppressor and highlight its therapeutic potential as a molecular target for combating HCC.

IMPACT AND IMPLICATIONS: We have identified ADCY7 and exosomal ADCY7 as potential therapeutic targets for inhibiting HCC metastasis. Our experimental results indicated that ADCY7 could induce the ubiquitination and degradation of N-cadherin by acting as a molecular scaffold to enhance the interaction between N-cadherin and the E3 ubiquitin ligase SMURF2, consequently impeding HCC metastasis. Therefore, ADCY7 holds great promise as a therapeutic target for HCC.