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Abstract Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of Kras G12D -driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

Introduction: Angiogenesis is an essential feature of liver cancer. Tumor hypoxia results from abnormal vessel architecture. Numerous studies have sufficiently demonstrated that Tanshinone IIA (Tan IIA) can increase blood flow and enhance microcirculation. The objectives of this study are to: 1 assess the impact of Tan IIA on tumor angiogenesis and architecture, 2 determine the impact of Tan IIA on tumor hypoxia and susceptibility to Sorafenib, and 3 clarify the relevant mechanisms.Methods: CCK8 and flow cytometry measured cell proliferation and apoptosis, respectively. Tube creation assay was used to investigate medication effects on angiogenesis and structure. Drug effects on tumor development, metastasis, and hypoxic tumor microenvironment are assessed in an orthotopic xenograft model of liver tumors. Protein expression was measured by Western blotting and immunohistochemistry.Results: Our results demonstrated that Tan IIA could not reduce tumor proliferation or enhance Sorafenib’s anti-tumor effect in vitro. Nevertheless, it can prevent Sorafenib from demolishing the typical vascular structure and aid sorafenib in blocking the recruitment of vascular endothelial cells by liver cancer cells. Although Tan IIA cannot inhibit tumor growth in vivo, it can significantly boost Sorafenib’s inhibitory effect on liver cancer, alleviate tumor microenvironment hypoxia, and minimize lung metastasis. This effect may be achieved by reducing HIF-1α and HIF-2α expression via the PI3K-AKT signal pathway.Discussion: Our results reveal the mechanism of Tan IIA in normalizing tumor blood vessels, provide innovative concepts and approaches to overcome chemotherapy resistance, and provide a theoretical basis for the clinical transformation and usage of Tan IIA.

BackgroundPhosphoinositide 3-kinases (PI3Ks) are lipid enzymes that regulate a wide range of intracellular functions. In contrast to Class I and Class III PI3K, which have more detailed descriptions, Class II PI3K has only recently become the focus of functional research. PIK3C2A is a classical member of the PI3Ks class II. However, the role of PIK3C2A in cancer prognosis and progression remains unknown.MethodsThe expression pattern and prognostic significance of PIK3C2A in human malignancies were investigated using multiple datasets and scRNA-seq data. The PIK3C2A expression in renal clear cell carcinoma (KIRC) was then validated utilizing Western blot. The functional role of PIK3C2A in KIRC was assessed using combined function loss experiments with in vitro experiments. Furthermore, the correlation of PIK3C2A expression with tumor immunity was investigated in KIRC. The TCGA database was employed to investigate PIK3C2A functional networks.ResultsSignificant decrease in PIK3C2A expression in KIRC, demonstrated that it potentially influences the prognosis of diverse tumors, particularly KIRC. In addition, PIK3C2A was significantly correlated with the T stage, M stage, pathologic stage, and histologic grade of KIRC. Nomogram models were constructed and used to predict patient survival based on the results of multivariate Cox regression analysis. PIK3C2A knockdown resulted in significantly increased KIRC cell proliferation. Of note, PIK3C2A expression demonstrated a significant correlation with the infiltrating levels of primary immune cells in KIRC.ConclusionThese findings support the hypothesis that PIK3C2A is a novel biomarker for tumor progression and indicates dynamic shifts in immune infiltration in KIRC. Furthermore, aberrant PIK3C2A expression can influence the biological activity of cancer cells.

Glucocorticoids and glucocorticoid receptor (GR) signalling can suppress anti-tumour immunity. Here the authors show that GR activates PD-L1 expression and represses MHC-I expression in pancreatic cancer cells, while GR inhibition enhances anti-tumour immunity and sensitises the cancer cells to immunotherapy.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive solid malignant tumors worldwide. Increasing investigations demonstrate that long non-coding RNAs (lncRNAs) expression is abnormally dysregulated in cancers. It is crucial to identify and predict the prognosis of patients for the selection of further therapeutic treatment.Methods: PDAC lncRNAs abundance profiles were used to establish a signature that could better predict the prognosis of PDAC patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied to establish a multi-lncRNA signature in the TCGA training cohort (N = 107). The signature was then validated in a TCGA validation cohort (N = 70) and another independent Fudan cohort (N = 46).Results: A five-lncRNA signature was constructed and it was significantly related to the overall survival (OS), either in the training or validation cohorts. Through the subgroup and Cox regression analyses, the signature was proven to be independent of other clinic-pathologic parameters. Receiver operating characteristic curve (ROC) analysis also indicated that our signature had a better predictive capacity of PDAC prognosis. Furthermore, ClueGO and CluePedia analyses showed that a number of cancer-related and drug response pathways were enriched in high risk groups.Conclusions: Identifying the five-lncRNA signature (RP11-159F24.5, RP11-744N12.2, RP11-388M20.1, RP11-356C4.5, CTC-459F4.9) may provide insight into personalized prognosis prediction and new therapies for PDAC patients.

Paired box 6 (PAX6) plays a significant role in the development of human neuroectodermal epithelial tissues. Previous studies have suggested that the PAX6 promoter is hypermethylated in breast cancer and that it is involved in breast cancer cell proliferation. The present study aimed to investigate the expression of PAX6 in invasive breast cancer tissues, and to evaluate its prognostic significance. Immunohistochemistry (IHC) was used to detect PAX6 expression on a breast cancer tissue microarray containing tissues from 111 patients. Associations of PAX6 expression with staging and prognosis were analyzed. PAX6 was mainly expressed in the nucleus. The PAX6 staining intensity was not associated with age, histological grade, lymph node status, tumor size, or progesterone receptor and human epidermal growth factor receptor 2 expression (all P>0.05). A high level of PAX6 staining was more frequent in estrogen receptor (ER)-negative cases compared with ER-positive cases (43.9 vs. 25.7%; P=0.049). After a median follow-up time of 110 months, the patients with low PAX6 expression exhibited an improved survival rate compared with the patients with high PAX6 expression (P<0.001). Cox analysis showed a worse survival rate in the patients with high PAX6 staining (hazard ratio, 3.458; 95% confidence interval, 1.575-7.593; P=0.002). In conclusion, high tumor PAX6 staining intensity by IHC was associated with a poor prognosis in breast cancer patients. [ABSTRACT FROM AUTHOR]