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Gemcitabine (GEM) is the gold-standard therapeutic regimen for patients with pancreatic cancer (PC); however, patients may receive limited benefits due to the drug resistance of GEM. LncRNA SNHG6 is reported to play key roles in drug resistance, but its role and molecular mechanism in PC remain incompletely understood. We found that LncRNA SNHG6 is drastically downregulated in GEM-resistant PC and is positively correlated with the survival of PC patients. With the help of bioinformatic analysis and molecular approaches, we show that LncRNA SNHG6 can sponge miR-944, therefore causing the upregulation of the target gene KPNA5. In vitro experiments showed that LncRNA SNHG6 and KPNA5 suppress PC cell proliferation and colony formation. The Upregulation of LncRNA SNHG6 and KPNA5 increases the response of GEM-resistant PANC-1 cells to GEM. We also show that the expression of KPNA5 is higher in patients without GEM resistance than in those who developed GEM resistance. In summary, our findings indicate that the LncRNA SNHG6/miR944/KPNA5 axis plays a pivotal role in overcoming GEM resistance, and targeting this axis may contribute to an increasing of the benefits of PC patients from GEM treatment.

Background Abnormal protein localization due to disrupted nucleoplasmic transport is common in tumor cells, but its mechanisms are not well understood. Nuclear pore complexes and nuclear transporter proteins are crucial for protein transport between the nucleus and cytoplasm. Evidence increasingly shows that abnormal expression of karyopherin family proteins disrupts protein translocation, affecting processes like cell differentiation, proliferation, apoptosis, and transcriptional regulation. However, their functions and roles in ovarian cancer remain unclear. Methods The expression level of KPNA5 in ovarian cancer tissues and cells was detected by IHC, Western blot, and qPCR. CCK‐8 and colony formation assays were used to assess cell proliferation ability. Transwell assay was conducted to determine cell migration and invasion capacity. A xenograft model was used to assess the effect of KPNA5 on tumor growth in vivo. Results KPNA5 expression is downregulated in ovarian cancer (OC) tissues. Low KPNA5 levels were associated with poor survival in OC patients, validated by an OC tissue sample cohort. Overexpression of KPNA5 significantly suppressed OC cell proliferation, tumor growth, and invasion in both in vitro and in vivo studies. Mechanistically, KPNA5 recognizes nuclear localization signals (NLSs) in PTPN4, mediating its nuclear transport and inhibiting STAT3 phosphorylation and its downstream signaling pathway. Similarly, PTPN4 overexpression reduced OC cell viability and invasion, also suppressing STAT3 phosphorylation. Conclusions Our findings identify KPNA5 as a tumor suppressor in OC, presenting a potential therapeutic target for OC treatment.