Syntaxin6 contributes to hepatocellular carcinoma tumorigenesis via enhancing STAT3 phosphorylation.

BACKGROUND: Syntaxin6 (STX6) is a SNARE (Soluble N-ethylmaleimide-sensitive factor attachment protein receptors) protein complex located in the trans-Golgi network and endosomes, which is closely associated with a variety of intracellular membrane transport events. STX6 has been shown to be overexpressed in a variety of human malignant tumors such as esophageal, colorectal, and renal cell carcinomas, and participates in tumorigenesis and development. METHODS: Based on clinical public database and clinical liver samples analysis, the expression of STX6 in hepatocellular carcinoma (HCC) tissues was investigated. The effects of STX6 on proliferation, migration and invasion of HCC cell in vitro and in vivo were evaluated through gain- and loss-of-function studies. We further performed RNA-seq analysis and protein interactome analysis, to further decifer the detailed mechanisms of STX6 in the regulation of the JAK-STAT pathway in HCC. RESULTS: STX6 expression was upregulated in HCC tissues and its expression was highly correlated with the high histological grade of the tumor. STX6 promoted HCC cell proliferation, migration and invasion both in vitro and in vivo. Mechanistically, STX6 mediated tumor progression depending on promoting the activation of JAK-STAT signaling pathway. Receptor for activated protein kinase C (RACK1) as an essential adaptor protein mediating STX6 regulation of JAK-STAT pathway. Specifically, STX6 interacted with RACK1 and then recruited signal transducer and activator of transcription 3 (STAT3) to form a protein-binding complex and activates STAT3 transcriptional activity. CONCLUSIONS: This study provided a novel concept that STX6 exerted oncogenic effects by activating the STAT3 signaling pathway, and STX6 might be a promising therapeutic target for HCC.

The efficacy and safety of conventional transcatheter arterial chemoembolization combined with PD-1 inhibitor and anti-angiogenesis tyrosine kinase inhibitor treatment for patients with unresectable hepatocellular carcinoma: a real-world comparative study.

Aim: We sought to evaluate the efficacy and safety of conventional transcatheter arterial chemoembolization (cTACE) sequentially combined with systemic treatment by programmed cell death protein 1 (PD-1) inhibitor and anti-angiogenesis tyrosine kinase inhibitor (Anti-angiogenesis TKI) in patients with unresectable hepatocellular carcinoma (HCC). Materials and methods: One hundred and forty-seven advanced HCC patients who received PD-1 inhibitors and TKIs as first-line systemic treatment between August 2019 and April 2021 were collected retrospectively. Fifty-four patients were finally included and divided into cTACE and no-cTACE groups, according to whether cTACE treatment was performed within 8 weeks before systemic treatment. The tumor objective response ratio (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were compared between the groups. Significant factors affecting PFS and OS were determined by Cox regression. Results: Thirty-one patients received cTACE followed by systemic treatment and 23 patients received systemic treatment only. The ORRs of the cTACE group were 48.4% (after two cycles of systemic treatment) and 51.6% (after four cycles of systemic treatment), while those of the no-cTACE group were only 17.4% and 21.7%. cTACE patients also had a longer median PFS (11.70 vs. 4.00 months, P = 0.031) and median OS (19.80 vs. 11.6 months, P = 0.006) than no-cTACE patients. Regression analyses indicated that cTACE therapy and Eastern Cooperative Oncology Group performance status were independent risk factors for PFS and OS. AEs by type were similar between the cTACE and no-cTACE groups, except for liver function injury, which was more common among cTACE patients. Fourteen patients suffered with grade 1-2 of rash in 21 patients with objective response, while only 10 patients suffered with rash in 33 patients without objective response, the adjusted hazard ratio (HR) was 4.382 (1.297-14.803). Conclusions: The combination of cTACE and PD-1 inhibitors and anti-angiogenesis TKIs as therapy significantly improved markers of treatment efficacy, including ORR, PFS, and OS, in unresectable HCC patients, while no more serious AEs recorded in this population compared to those receiving systemic treatment alone. Skin rash might be a predict factor to the efficacy of PD-1 inhibitors and TKI treatment.

Tripartite motif-containing protein 11 promotes hepatocellular carcinogenesis through ubiquitin-proteasome-mediated degradation of pleckstrin homology domain leucine-rich repeats protein phosphatase 1.

BACKGROUND AND AIMS: HCC is one of the main types of primary liver cancer, with high morbidity and mortality and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC remain open for study. APPROACH AND RESULTS: Through clinical analysis, we found that the expression of TRIM11 was up-regulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade, and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with pleckstrin homology domain leucine-rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1 and thus promoted activation of the protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. CONCLUSIONS: Our study confirmed that TRIM11 plays an oncogenic role in HCC through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of HCC.

Prediction of Hepatocellular Carcinoma Response to Transcatheter Arterial Chemoembolization: A Real-World Study Based on Non-Contrast Computed Tomography Radiomics and General Image Features.

OBJECTIVE: To construct a predictive model of short-term response and overall survival for transcatheter arterial chemoembolization (TACE) treatment in hepatocellular carcinoma (HCC) patients based on non-contrast computed tomography (NC-CT) radiomics and clinical features. METHODS: Ninety-four HCC patients who underwent CT scanning 1 week before the first TACE treatment were retrospectively recruited and divided randomly into a training group (n = 47) and a validation group (n = 47). NC-CT radiomics data were extracted using MaZda software, and the compound model was calculated from radiomics and clinical features by logistic regression. The performance of the different models was compared by examining the area under the receiver operating characteristic curve (AUC). The prediction of prognosis was evaluated using survival analysis. RESULTS: Thirty NC-CT radiomic features were extracted and analyzed. The compound model was formed using four NC-CT run-length matrix (RLM) features and general image features, which included the maximum diameter (cm) of the tumor and the number of tumors (n). The AUCs of the model for TACE response were 0.840 and 0.815, whereas the AUCs of the six-and-twelve grade were 0.754 and 0.750 in the training and validation groups, respectively. HCC patients were divided into two groups using the cutoff value of the model: a group in which the TACE-response led to good survival and a group in which TACE-nonresponse caused poor prognosis. CONCLUSION: Radiomic features from NC-CT predicted TACE-response. The compound model generated by NC-CT radiomics and clinical features is effective and directly predicts TACE-response and overall survival. The model may be used repeatedly and is easy to operate.

TELO2 induced progression of colorectal cancer by binding with RICTOR through mTORC2.

Colorectal cancer (CRC) is a common cancer worldwide, and its treatment strategies are limited. The underlying mechanism of CRC progression remains to be determined. Telomere maintenance 2 (TELO2) is a mTOR­interacting protein. Both the role and molecular mechanism of TELO2 in cancer progression remain unknown. In this study, the gene expression database of normal and tumor tissue, in addition to western blot analysis, and immunohistochemistry (IHC) were used to determine the expression and location of TELO2 in CRC and normal tissues. Clinical features of a tissue array were collected and analyzed. WST­1, soft agar, flow cytometry, wound healing, and invasion assays were employed to verify the role of TELO2 in the growth, cell cycle, migration, and invasion of CRC cells. The correlation between TELO2 and RICTOR (rapamycin­insensitive companion of mTOR) was analyzed by bioinformatics, IHC, and immunoprecipitation. Normal and serum­deprived cells were collected to detect the protein level of TELO2 and its downstream effectors. The results revealed that TELO2 was significantly upregulated in CRC, and TELO2 inhibition significantly restrained the growth, cell cycle, and metastasis of CRC cells. TELO2 overexpression correlated with age, lymph node metastasis, and TNM stage of CRC patients. In addition, TELO2 was positively correlated with RICTOR in CRC and induced tumor progression mainly via RICTOR with serum in culture. RICTOR induced the degradation of TELO2 upon serum deprivation in an mTOR­independent manner. These findings indicate that TELO2 promotes tumor progression via RICTOR in a serum­dependent manner, which may be a potential therapeutic target for CRC.