PIN1 promotes the metastasis of cholangiocarcinoma cells by RACK1-mediated phosphorylation of ANXA2.

BACKGROUND: Cholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood. METHODS: In this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques. RESULTS: Our findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model. CONCLUSION: Overall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.

MAD2 activates IGF1R/PI3K/AKT pathway and promotes cholangiocarcinoma progression by interfering USP44/LIMA1 complex.

Spindle assembly checkpoint (SAC) plays an essential part in facilitating normal cell division. However, the clinicopathological and biological significance of mitotic arrest deficient 2 like 1 (MAD2/MAD2L1), a highly conserved member of SAC in cholangiocarcinoma (CCA) remain unclear. We aim to determine the role and mechanism of MAD2 in CCA progression. In the study, we found up-regulated MAD2 facilitated CCA progression and induced lymphatic metastasis dependent on USP44/LIMA1/PI3K/AKT pathway. MAD2 interfered the binding of USP44 to LIMA1 by sequestrating more USP44 in nuclei, causing impaired formation of USP44/LIMA1 complex and enhanced LIMA1 K48 (Lys48)-linked ubiquitination. In therapeutic perspective, the data combined eleven cases of CCA PDTX model showed that high-MAD2 inhibits tumor necrosis and diminishes the inhibition of cell viability after treated with gemcitabine-based regimens. Immunohistochemistry (IHC) analysis of tissue microarray (TMA) for CCA patients revealed that high-MAD2, low-USP44 or low-LIMA1 level are correlated with worse survival for patients. Together, MAD2 activates PI3K/AKT pathway, promotes cancer progression and induces gemcitabine chemo-resistance in CCA. These findings suggest that MAD2 might be an excellent indicator in prognosis analysis and chemotherapy guidance for CCA patients.

KIF14 promotes proliferation, lymphatic metastasis and chemoresistance through G3BP1/YBX1 mediated NF-κB pathway in cholangiocarcinoma.

Cholangiocarcinoma (CCA), a highly lethal and fetal cancer derived from the hepatobiliary system, is featured by aggressive growth and early lymphatic metastasis. Elucidating the underlying mechanism and identifying the effective therapy are critical for advanced CCA patients. In the study, we detected that KIF14 was upregulated in CCA samples, especially in patients with lymph node metastasis and vascular invasion. CCA patients with higher KIF14 were associated with worse overall survival and recurrence-free survival after surgery. Gain-of and loss-of function studies showed that KIF14 enhanced CCA cells proliferation, migration, invasion and lymphatic metastasis whereas its silencing abolished the effects in vivo and in vitro. Mechanistic investigation showed that KIF14 bound to the G3BP1/YBX1 complex and facilitated their interaction, causing increased activity of the NF-κB promoter and activation of NF-κB pathway. Furthermore, increased KIF14 level enhanced chemotherapy-resistance to gemcitabine-based regimen and induced immunosuppressive microenvironment. In addition, KIF14 was direct target of HNF4A and inversely regulated by HNF4A. Together, these findings suggested that KIF14 could be a potential oncogene and a good indicator in predicting prognosis and chemotherapy guidance for CCA patients.