Background: miR-27b-3p is dysregulated in many cancers, but its expression, clinical role, and mechanism in pancreatic cancer are not fully understood. Objective: This study aimed to evaluate the clinical value of miR-27b-3p in PC and its role in pancreatic cancer (PC) progression by targeting PPARG. Method: qRT-PCR was used to measure miR-27b-3p and PPARG levels in 106 paired PC tissues and adjacent non-tumor tissues, and in PC cell lines (PANC-1, SW1990, BxPC-3, AsPC-1) and HPDE cells. Kaplan-Meier and multivariate Cox analyses assessed miR-27b-3p prognostic value. CCK-8 and Transwell assays evaluated the impact of miR-27b-3p inhibition on PC cell function. Dual-luciferase reporter and Pearson correlation analyses confirmed the targeting of PPARG by miR-27b-3p. A PPARG knockdown rescue experiment verified that miR-27b-3p function depends on PPARG. Results: miR-27b-3p was highly expressed in PC tissues and cell lines and linked to lymph node metastasis, distant metastasis, elevated CA19-9 levels, and poor overall survival. Multivariate Cox analysis showed high miR-27b-3p expression as an independent predictor of poor prognosis. In vitro, miR-27b-3p inhibition suppressed PANC-1 cell proliferation, migration, and invasion. PPARG was a direct target of miR-27b-3p and was downregulated at both mRNA and protein levels. A negative correlation was found between miR-27b-3p and PPARG mRNA in PC tissues. PPARG knockdown reversed the effects of miR-27b-3p inhibition, confirming functional dependence. Conclusion: miR-27b-3p functions as an oncogenic miRNA in PC by targeting PPARG and may be a prognostic biomarker and therapeutic target.
INTRODUCTION:The oncologic impact of lymph node dissection (LND) for intrahepatic cholangiocarcinoma (iCCA) remains unclear. We hypothesized that the prognostic relevance of LND may vary according to tumor burden. Therefore, this study sought to evaluate the interaction between tumor burden and adequate LND among patients who underwent curative-intent resection for iCCA. METHODS:Patients who underwent curative-intent liver resection for iCCA were identified from a large international multi-institutional database. Overall survival (OS) was evaluated using multivariable Cox regression models that included an interaction term between tumor burden score (TBS) and adequate LND. RESULTS:Among 1,558 patients, 872 (56.0%) underwent LND and 322 (20.7%) underwent adequate LND, defined as retrieval of at least six lymph nodes. The median TBS was 6.1 (interquartile range [IQR] 4.1-8.6). On multivariable Cox regression analysis, a significant interaction was observed between TBS and adequate LND (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.87-0.95, p < 0.001). Among 542 (34.8%) patients with TBS < 5.0, adjusted OS did not differ according to adequate LND status (HR 1.23, 95% CI 0.86-1.76, p = 0.265). In contrast, among 1,016 (65.2%) patients with TBS ≥ 5.0, adequate LND was associated with improved adjusted OS (HR 0.65, 95% CI 0.51-0.82, p < 0.001). Similar findings were observed for recurrence-free survival (RFS). CONCLUSIONS:The prognostic relevance of adequate LND in patients undergoing curative-intent resection for iCCA appears to vary according to tumor burden. Adequate LND was associated with improved OS and RFS among patients with high TBS, but not among those with low TBS.
Immunotherapy has revolutionized cancer treatment, yet its efficacy in hepatocellular carcinoma (HCC) remains limited and the mechanisms of resistance are poorly defined. Using in vivo CRISPR-Cas9 screens, we identify serine/threonine kinase 40 (STK40) as a previously unrecognized regulator of immune evasion. Stk40 ablation synergizes with PD-1 blockade to induce tumor regression. Hepatocyte-specific Stk40 deletion abolishes tumorigenesis in hydrodynamic plasmid-driven HCC models. Mechanistically, STK40 scaffolds the COP1 ubiquitin ligase to promote interferon gamma receptor 1 (IFNGR1) degradation. Genetic depletion of Stk40 stabilizes IFNGR1, restoring tumor cell sensitivity to T cell cytotoxicity. Concurrently, Stk40 loss triggers autonomous GM-CSF secretion, enhancing the infiltration and activation of conventional type 1 dendritic cells, which promotes antigen cross-presentation and CD8+ T cell activation. Pharmacological inhibition of STK40 using LNP-siRNA, combined with PD-1 blockade, elicits potent anti-tumor responses across multiple cancer types. These findings establish STK40 as a dual-action therapeutic target to overcome resistance to anti-tumor immunity.
PTC596 has been studied in advanced solid tumors in clinical trials. However, the effects of PTC596 alone or in combination with programmed cell death protein-1 (PD1) blockade in hepatocellular carcinoma (HCC) remain unclear. Subcutaneous tumor models in both Balb/c and C57BL/6 mice were used to evaluate the effects of PTC596 alone or combined with an anti-PD1 antibody (anti-PD1) on tumor growth control, survival, and tumor-infiltrating immune cells, and the underlying mechanism was investigated by immunofluorescence, flow cytometry, RNA sequencing and immunohistochemistry. We found PTC596 not only killed HCC cells in vitro but also controlled H22 and Hepa1-6 tumor growth in vivo. PTC596 promoted the infiltration of CD8+ T-cells in H22 and Hepa1-6 models. Importantly, combination therapy (PTC596 plus anti-PD1) showed superior antitumor efficacy and prolonged mouse survival. Moreover, combination therapy induced robust antitumor immune activity by activating mature dendritic cells, CD8+ T-cells, natural killer cells, inflammatory monocytes, and total macrophages, while suppressing the infiltration of B cells and M2-type macrophages. RNA sequencing confirmed that the antitumor effects of PTC596 alone or plus anti-PD1, relied on the regulation of inflammation- and immune-associated pathways. Furthermore, combination therapy induced long-term immunological memory in 'cured' mice, as these mice were unaffected by tumor rechallenge after the original tumors were eliminated. Therefore, PTC596 is not only an effective antitumor drug for HCC but also supports the formation of a favorable tumor microenvironment that enhances the effect of PD1 blockade. This study supports that PTC596 combined with PD1 blockade could be a promising strategy for HCC.
Hilar cholangiocarcinoma (HCCA) is a malignant tumor at the hepatic hilum with poor prognosis and survival despite surgical resection. While existing staging systems, including AJCC, Gazzaniga T, MSKCC and Blumgart, provide prognostic frameworks, their predictive accuracy remains suboptimal. This study aimed to develop and validate a novel machine learning-based postoperative staging system to predict overall survival (OS) and enhance prognostic stratification for HCCA patients undergoing surgery. We retrospectively analyzed 426 HCCA patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital (EHBH) between February 2011 and May 2022. Seventy clinical variables, encompassing demographic characteristics, laboratory parameters, and imaging data, were evaluated. Eight machine learning algorithms were employed for feature selection and model development. A multivariable Cox regression analysis was subsequently performed to establish a staging system. External validation was performed using an independent cohort of 88 HCCA patients for further evaluation. The final model incorporated key prognostic factors including tumor stage, vascular invasion, and tumor biomarkers (CA199,CA125,CEA). The CatBoost algorithm demonstrated superior performance on the validation set (AUC = 0.88). The developed EHBH-HCCA staging system based on CatBoost stratified patients into four risk levels, significantly differentiating 3-year survival outcomes (P < 0.001). Median survival times were: Level I (> 36 months), Level II (25.0 months), Level III (18.0 months), and Level IV (< 12 months). The system showed superior discrimination (Harrell’s C-index: 0.717, 95
