Activated pancreatic stellate cells (PSCs) are the main cells involved in chronic pancreatitis and pancreatic intraepithelial neoplasia lesion (PanIN). Fine-tuning the precise molecular targets in PSC activation might help the development of PSC-specific therapeutic strategies to tackle progression of pancreatic cancer-related fibrosis. miR-301a is a pro-inflammatory microRNA known to be activated by multiple inflammatory factors in the tumor stroma. Here, we show that miR-301a is highly expressed in activated PSCs in mice, sustained tissue fibrosis in caerulein-induced chronic pancreatitis, and accelerated PanIN formation. Genetic ablation of miR-301a reduced pancreatic fibrosis in mouse models with chronic pancreatitis and PanIN. Cell proliferation and activation of PSCs was inhibited by downregulation of miR-301a via two of its targets, Tsc1 and Gadd45g. Moreover, aberrant PSC expression of miR-301a and Gadd45g restricted the interplay between PSCs and pancreatic cancer cells in tumorigenesis. Our findings suggest that miR-301a activates two major cell proliferation pathways, Tsc1/mTOR and Gadd45g/Stat3, in vivo, to facilitate development of inflammatory-induced PanIN and maintenance of PSC activation and desmoplasia in pancreatic cancer.

Background: Hepatocellular carcinoma (HCC), one of the highest causes of cancer-associated death, has effective treatments, especially for patients with advanced HCC. Circadian rhythm participates in several important physiological functions, and its chronic disruption results in many disordered diseases, including cancer. However, the role of circadian rhythm in the overall survival (OS) of patients with HCC remains unclear. Methods: We investigated the expression, copy number variation (CNV), and mutation profiles of core circadian clock genes in normal and tumor tissues. We developed and validated a messenger RNA signature (mRNASig) based on prognostic circadian clock genes. A set of bioinformatic tools were applied for functional annotation and tumor-associated microenvironment (TME) analysis. Results: Core circadian clock genes were disrupted in terms of the transcription and CNV of HCC samples. The mRNASig, including NPAS2, NR1D1, PER1, RORC, and TIMELESS, was constructed. We divided patients with HCC into high-risk group and low-risk group based on the median value of the risk score. The high-risk group had a poorer prognosis than the low-risk group. The high-risk group was associated with malignant processes (e.g., proliferation, oncogenic pathway, DNA repair), metabolism, and tumor mutational burden (TMB). Surprisingly, the low-risk group was associated with enriched angiogenesis and was linked to enhanced response to sorafenib. Moreover, the high-risk group showed poor infiltration of CD8 T cells and natural killer cells accompanied by higher expression of CTLA4, PDCD1, TIGIT, and TIM3. Additionally, the mRNASig was associated with TMB. Conclusions: The mRNASig based on core circadian clock genes is a potential prognostic signature and therapeutic strategy and is significantly associated with the malignant biology of HCC.

BACKGROUND Biliary stone disease is a highly prevalent condition and a leading cause of hospitalization worldwide. Hepatolithiasis with associated strictures has high residual and recurrence rates after traditional multisession percutaneous transhepatic cholangioscopic lithotripsy (PTCSL). AIM To study one-step PTCSL using the percutaneous transhepatic one-step biliary fistulation (PTOBF) technique guided by three-dimensional (3D) visualization. METHODS This was a retrospective, single-center study analyzing, 140 patients who, between October 2016 and October 2023, underwent one-step PTCSL for hepatolithiasis. The patients were divided into two groups: The 3D-PTOBF group and the PTOBF group. Stone clearance on choledochoscopy, complications, and long-term clearance and recurrence rates were assessed. RESULTS Age, total bilirubin, direct bilirubin, Child-Pugh class, and stone location were similar between the 2 groups, but there was a significant difference in bile duct strictures, with biliary strictures more common in the 3D-PTOBF group (P = 0.001). The median follow-up time was 55.0 (55.0, 512.0) days. The immediate stone clearance ratio (88.6% vs 27.1%, P = 0.000) and stricture resolution ratio (97.1% vs 78.6%, P = 0.001) in the 3D-PTOBF group were significantly greater than those in the PTOBF group. Postoperative complication (8.6% vs 41.4%, P = 0.000) and stone recurrence rates (7.1% vs 38.6%, P = 0.000) were significantly lower in the 3D-PTOBF group. CONCLUSION Three-dimensional visualization helps make one-step PTCSL a safe, effective, and promising treatment for patients with complicated primary hepatolithiasis. The perioperative and long-term outcomes are satisfactory for patients with complicated primary hepatolithiasis. This minimally invasive method has the potential to be used as a substitute for hepatobiliary surgery.