ERK‐mediated transcriptional activation of Dicer is involved in gemcitabine resistance of pancreatic cancer

Abstract

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)-producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine-resistant PANC-1 (PANC-1/GEM) cells compared with parental PANC-1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC-1/GEM cells; consistently, overexpression of Dicer in PANC-1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC-1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Dicer-mediated miR-200b expression contributes to cell migratory/invasive abilities and cancer stem cells properties of breast cancer cells

“…We noted significantly lower Dicer expression in the highly invasive cells. Moreover, some studies have reported that Dicer plays an important role in regulating tumor progression in different types of cancer [ 8 , 23 ]. Thus, in the present study, to investigate whether Dicer affects the migration, invasion, and CSCs properties of breast cancer cells, we established stable Dicer-silenced (MCF-7/shDicer and MDA-MB-231/shDicer) cells, respectively ( Figure 3A ).…”

“…Moreover, the overexpression of Dicer decreased the cell proliferation, migration and invasion of hepatocellular carcinoma (HCC) cells through the vascular endothelial growth factor signaling pathway [ 38 ]. On the contrary, Dicer knockdown increased drug sensitivity in gemcitabine-resistant pancreatic cancer cells [ 23 ]. In the current study, we established highly invasive cell lines to investigate the molecular mechanisms underlying cell migration and invasion.…”

Genome-Wide CRISPR Screening Identifies DCK and CCNL1 as Genes That Contribute to Gemcitabine Resistance in Pancreatic Cancer

“…STAT3 is actively involved in cell growth and survival [32]. Changes to the phosphorylation of Erk [33][34][35], Akt [36][37][38], and STAT3 [39,40] could alter cancer cells' sensitivity to gemcitabine treatment. In our study, the phosphorylation of Erk, Akt, and STAT3 was hyperactivated after we had knocked out CCNL1 in TB32047 and PANC1 cells, suggesting that the loss of CCNL1 induces resistance to gemcitabine treatment by activating the ERK/AKT/STAT3 survival pathway.…”

Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer

“…When resistant clones were selected by incubating cells with increasing concentrations of gemcitabine for several passages, whole-proteome analysis revealed a significant up-regulation of calmodulin 2 (CALM2), consistent with our prior sequencing data. Pharmacologic inhibition of calcium-dependent calmodulin activation restored gemcitabine sensitivity in vitro, which further single-cell RNA-sequencing analysis revealed was associated with the inhibition of prosurvival ERK signaling, a known driver of gemcitabine resistance ( 13 – 16 ). This was recapitulated using the calcium chelator BAPTA-AM, which similarly mitigated ERK activation and restored gemcitabine sensitivity in vitro.…”