E3 ubiquitin ligase TRIM29 promotes pancreatic cancer growth and progression via stabilizing Yes-associated protein 1.

BACKGROUND: Pancreatic cancer (PC) is one of the most fatal digestive system cancers. tripartite motif-29 (TRIM29) has been reported as oncogene in several human cancers. However, the precise role and underlying signal cascade of TRIM29 in PC progression remain unclear. METHODS: Western blot, qRT-PCR and immunohistochemistry were used to analyze TRIM29 and Yes-associated protein 1 (YAP1) levels. CCK8 assays, EdU assays and flow cytometry were designed to explore the function and potential mechanism of TRIM29 and YAP1 in the proliferation of PC. Next, a nude mouse model of PC was established for validating the roles of TRIM29 and YAP1 in vivo. The relationship among TRIM29 and YAP1 was explored by co-immunoprecipitation and in vitro ubiquitination assay. RESULTS: TRIM29 and YAP1 was significantly upregulated in PC patient samples, and TRIM29 expression was closely related to a malignant phenotype and poorer overall survival (OS) of PC patients. Functional assays revealed that TRIM29 knockdown suppresses cell growth, arrests cell cycle progression and promotes cell apoptosis of PC cells in vivo and in vitro. Furthermore, the rescue experiments demonstrated that TRIM29-induced proliferation is dependent on YAP1 in PC cells. Mechanistically, TRIM29 regulates YAP1 expression by directly binding to YAP1, and reduced its ubiquitination and degradation. CONCLUSION: Taken together, these results identify a novel mechanism used by PC growth, and provide insight regarding the role of TRIM29 in PC.

SLC25A22 promotes proliferation and metastasis by activating MAPK/ERK pathway in gallbladder cancer.

BACKGROUND: SLC25A22, a member of mitochondrial carrier system (MCS) family encoding a mitochondrial glutamate transporter, has been reported to have vital roles in promoting proliferation and migration in cancer. Gallbladder cancer (GBC) is the most common biliary tract malignancy and has a poor prognosis. We aimed to determine the expression and function of SLC25A22 in GBC. METHODS: Immunohistochemistry (IHC) staining analysis and quantitative real-time PCR (qRT-PCR) were conducted to determine the expression of SLC25A22 in GBC tissues. Human NOZ and GBC-SD cells were used to perform the experiments. The protein expression was detected by western-blot analysis. Cell viability was evaluated via CCK-8 assay and colony formation assay. Cell migration and invasion in vitro were investigated by wound healing and transwell assay. Annexin V/PI staining assay for apoptosis were measured by flow cytometry. The effect of SLC25A22 in vivo was conducted with subcutaneous xenograft. RESULTS: We indicated that the expression of SLC25A22 was significantly upregulated in GBC tumor tissues as well as cell lines. Downregulation of SLC25A22 inhibited GBC cell growth and proliferation in vitro and in vivo and also had an effect on metastasis of GBC cells through the EMT processes. In addition, inhibition of SLC25A22 promoted mitochondrial apoptosis via downregulating BCL-2 and upregulating cleaved PARP, Cytochrome-c, and BAX mediated by MAPK/ERK pathway. CONCLUSIONS: Our study identified that SLC25A22 promoted development of GBC activating MAPK/ERK pathway. SLC25A22 has a potential to be used as a target for cancer diagnosis of GBC and related therapies.