Anticancer and therapeutic efficacy of XPO1 inhibition in pancreatic ductal adenocarcinoma through DNA damage and modulation of miR-193b/KRAS/LAMC2/ERK/AKT signaling cascade.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and grave malignancies with confined and ineffective therapeutic options. XPO1 is a critical regulator of nuclear export and activation of tumor suppressor proteins. The present study evaluated the therapeutic potential and molecular mechanisms of XPO1 inhibition against PDAC. Firstly, we observed significant overexpression of XPO1 transcript in 179 PDAC patients than 171 normal pancreatic tissues in TCGA transcriptomic dataset. Higher XPO1 transcript levels displayed worse overall and disease-free survival. Further, we confirmed significant upregulation of XPO1 in a panel of PDAC cells. Eltanexor treatment resulted in significant inhibition of cell viability, clonogenic growth, migration, and epithelial-mesenchymal transition (EMT), along with the induction of cell cycle arrest. Mechanistically, eltanexor modulated the expression of key proteins including p21, p27, p53, cyclin B1, cyclin D1, c-Myc, N-cadherin, vimentin, E-cadherin associated with the cell viability, growth, cell cycle and EMT. Additionally, the eltanexor treatment resulted in marked increase in expression of γH2AX, and cleaved PARP, cleaved caspase-9 leading to induction of DNA damage and apoptosis of PDAC cells, respectively. Moreover, eltanexor treatment regulated the expression of key non-coding RNAs including miR193b, DINO, MALAT-1, H19, and SOX21-AS1 linked with tumorigenesis. Our results revealed a correlation among miR193b/KRAS/LAMC2, XPO1/KRAS, and LAMC2/KRAS. The findings also revealed that eltanexor treatment rescued the expression of miR193b which acts as a sponge for LAMC2 and KRAS resulting in the suppression of AKT/ERK downstream signaling cascade in PDAC. Interestingly, the combination of eltanexor with gemcitabine showed significant anticancer activity in PDAC cells. Altogether, our findings revealed the crucial role of XPO1 in modulating the expression of oncogenic proteins, ncRNAs, and DNA damage during PDAC progression as well as identified novel therapeutic miR-193b/KRAS/LAMC2/ERK/AKT axis.

Kirtonia A ，Pandya G ，Singh A ，Kumari R ，Singh B ，Kapoor S ，Khattar E ，Pandey AK ，Garg M ... -  《-》

Jorunnamycin A induces apoptosis in pancreatic ductal adenocarcinoma cells, spheroids, and patient-derived organoids by modulating KRAS-mediated survival pathways.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, frequently driven by oncogenic KRAS mutations. Among these, KRAS G12D is the most prevalent, contributing to chemoresistance and limiting the efficacy of current therapeutic strategies. This study investigates the therapeutic potential of jorunnamycin A (JA), a bioactive compound derived from the marine sponge Xestospongia, in PDAC. Molecular docking analyses were performed to assess JA's binding affinity for various KRAS protein variants. The synergistic effects of JA in combination with standard chemotherapeutic agents were evaluated using the Bliss independence model in pancreatic cancer cell lines and patient-derived PDAC organoids harboring distinct KRAS mutations. Furthermore, western blot analysis was performed to examine the impact the molecular mechanisms underlying JA's anticancer activity. JA demonstrated potent anticancer activity against PDAC cells, irrespective of their KRAS mutation status. In silico molecular docking and protein suppression studies indicated a strong binding affinity between JA and KRAS G12D. Synergistic interactions between JA and various PDAC chemotherapeutic agents, including oxaliplatin, SN-38, paclitaxel, 5-fluorouracil, and gemcitabine, were observed using the Bliss independence model. Notably, co-treatment with JA at a 10-fold lower concentration significantly enhanced the cytotoxicity of oxaliplatin, reducing its IC50 values around tenfold. This synergistic impact was further validated in both KRAS G12D spheroids and patient-derived PDAC organoids harboring KRAS G12D and other KRAS variants. Mechanistically, the JA-oxaliplatin combination enhanced caspase-3/7 activation, suppressed key KRAS-mediated survival pathways (STAT3, B/C-RAF, AKT, and ERK), and led to the downregulation of anti-apoptotic proteins (MCL-1 and BCL-2). These findings highlight JA as a promising therapeutic candidate for PDAC, particularly in the context of KRAS G12D-driven tumors. Further investigations into its pharmacokinetics and clinical feasibility are warranted to explore its full potential in PDAC treatment.

Khine HEE ，Suriya U ，Rungrotmongkol T ，Chamni S ，Lu Y ，Bénard A ，Lan B ，Mukhopadhyay D ，Chang D ，Biankin A ，Schneider-Stock R ，Grützmann R ，Sungthong R ，Pilarsky C ，Chaotham C ... -  《-》

Significant association of miRNA 34a with BRCA1 expression in pancreatic ductal adenocarcinoma: an insight on miRNA regulatory pathways in the Pakistani population.

Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive cancers, characterized by high mortality rates. Studies on various cancers across the globe indicate that regulatory miRNAs play a vital role in cellular signaling. However, the expression and interactions of these miRNAs in the Pakistani patients with PDAC is yet to be explored. Here, we aim to investigate a panel of four regulatory miRNAs (miRNA 34a, 30b, 142 and 137) in PDAC and their interaction with selected target proteins in the signaling pathway (KRAS, p53, BRCA1, APC). We conducted a study on 109 PDAC patients to analyze the selected miRNAs and protein targets. Formalin Fixed Paraffin Embedded (FFPE) tumor samples were obtained from the hospital's department of histopathology. After confirmation of diagnosis and appropriate tumor content, tissues were processed for RNA extraction. Based on the acceptable quality and quantity of RNA, 43 samples were proceeded for qRT-PCR. Relative expression of the miRNAs was determined through 2-[ΔΔCt] method. Further, FFPE tumor blocks were used to perform tissue sectioning followed by immunohistochemistry experiments. Stained slides were scored independently by two pathologists according to set criteria. Expression profiles revealed that miRNA 34a, 30b, and 142 showed high expression in approximately 69-70% of cases, while miRNA 137 had a lower high expression frequency (53.4%). Among protein biomarkers, KRAS, BRCA1, and APC were predominantly expressed, with high expression levels observed in 79.1%, 69.8%, and 51.2% of cases, respectively, whereas p53 showed positive expression in only 34.9% of cases. Statistical analysis showed that expression of miRNA 34a was significantly associated with the expression of BRCA1 (p = 0.034). No significant associations were observed for KRAS, p53, or APC with the selected miRNAs. Moreover, the expression of miRNA 34a independently showed significant association with miRNA 30b (p = 0.000) and miRNA 137 (p = 0.001). None of the miRNA showed an association with the overall survival, patient demographics or the clinicopathological characteristics. Our study highlights a potential bi-directional regulatory relationship between BRCA1 and miRNA 34a, suggesting that miRNA 34a may both respond to and influence BRCA1 activity within cellular signaling pathways. This complex interaction points to a layered regulatory network that could play a crucial role in tumor suppression in PDAC, underscoring the therapeutic potential of targeting this miRNA-protein crosstalk.

Ali SM ，Adnan Y ，Ahmad Z ，Chawla T ，Farooqui HA ，Adnan Ali SM ... -  《BMC CANCER》

Characterization of Epithelial-Mesenchymal and Neuroendocrine Differentiation States in Pancreatic and Small Cell Ovarian Tumor Cells and Their Modulation by TGF-β1 and BMP-7.

Ungefroren H ，von der Ohe J ，Braun R ，Gätje Y ，Lapshyna O ，Schrader J ，Lehnert H ，Marquardt JU ，Konukiewitz B ，Hass R ... -  《Cells》

Hypoxia-induced MIR31HG expression promotes partial EMT and basal-like phenotype in pancreatic ductal adenocarcinoma based on data mining and experimental analyses.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer, with a five-year survival rate below 8%. Its high mortality is largely due to late diagnosis, metastatic potential, and resistance to therapy. Epithelial-mesenchymal transition (EMT) plays a key role in metastasis, enabling cancer cells to become mobile. Partial EMT, where cells maintain both epithelial and mesenchymal traits, is more frequent in tumors than complete EMT and contributes to cancer progression. The long non-coding RNA MIR31 host gene (MIR31HG) has recently emerged as a critical factor in PDAC oncogenesis. This study aimed to investigate MIR31HG's role in partial EMT and its association with the basal-like PDAC subtype. We analyzed the relationship between MIR31HG expression, partial EMT, and the basal-like subtype of PDAC by integrating data from public databases. We reanalyzed public data from PDAC patient-derived organoids to assess MIR31HG expression and gene signatures under hypoxic and normoxic conditions. RNA sequencing and bioinformatics analyses, including gene set enrichment analysis (GSEA), were used to investigate differentially expressed genes and pathway enrichments. EMT, partial EMT, and hypoxia scores were calculated based on the expression levels of specific gene sets. We observed that MIR31HG overexpression strongly correlates with higher partial EMT scores and the stabilization of the epithelial phenotype in PDAC. MIR31HG is highly expressed in the basal-like subtype of PDAC, which exhibits partial EMT traits. Hypoxia, a hallmark of basal-like PDAC, was shown to significantly induce MIR31HG expression, thereby promoting the basal-like phenotype and partial EMT. In patient-derived organoids, hypoxic conditions increased MIR31HG expression and enhanced basal-like and partial EMT gene signatures, while normoxia reduced these expressions. These findings suggest that hypoxia-induced MIR31HG expression plays a crucial role in driving the aggressive basal-like subtype of PDAC. Our results indicate that MIR31HG is crucial in regulating PDAC progression, particularly in the aggressive basal-like subtype associated with hypoxia and partial EMT. Targeting the MIR31HG-mediated network may offer a novel therapeutic approach to combat hypoxia-driven PDAC.

Ko CC ，Yang PM 《-》