Glucocorticoid-induced microRNA-378 signaling mediates the progression of pancreatic cancer by enhancing autophagy

Liu, Li; Han, Shanshan; Xiao, Xi; An, Xuefeng; Gladkich, Jury; Hinz, Ulf; Hillmer, Stefan; Hoppe-Tichy, Torsten; Xu, Yi; Schaefer, Michael; Strobel, Oliver; Herr, Ingrid

doi:10.1038/s41419-022-05503-3

Cited by 12 publications

(8 citation statements)

References 64 publications

(77 reference statements)

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“…As we expected, these activated genes of ferroptosis such as PTGS2, [27] CHAC1 [27] and SAT1 [28] were up‐regulated while inhibited genes FADS2, [27] ALDH3 A1, [29] SCD, [28] KRT18, [30] LDHA, [31] HSPA8, [32] GPX4 and FTL were obviously down‐regulated, consistent with the negative regulation in the GSEA results. Besides, expressions of MAP1LC3B, [33] MAP1LC3B2, [33] SQSTM1/p62 [34] and BCL2L2, [35] which were contributed to autophagy progress, were also upregulated after Ir‐Bet treatment (Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium‐Betulin Immune Agonist

Lv,

Zheng,

et al. 2023

Angew Chem Int Ed

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Ferroptosis is a form of programmed cell death driven by iron‐dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal‐based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl (Ir‐Bet) was developed by a metal‐ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl]2Cl2 with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir‐Cp*) species as Ir‐Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa‐B (NF‐κB) activation of Ir‐Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir‐Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs).

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Section: Resultsmentioning

confidence: 99%

Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium‐Betulin Immune Agonist

Lv,

Zheng,

et al. 2023

Angew Chem Int Ed

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“…miRNAs are small non-coding RNA molecules that bind target mRNAs via complementary sequences in the 3'-UTR to inhibit their expression. Low expression of miR-378a-3p is closely associated with an unfavorable prognosis, which has been demonstrated in numerous different types of cancer cells, such as pancreatic cancer (35), ovarian cancer (36), and ESCC tissues (21). However, the results of previous studies involving the biological functions of miR-378 in tumor cells remain contested.…”

Section: Discussionmentioning

confidence: 99%

Upregulated miR‑378a‑3p expression suppresses energy metabolism and promotes apoptosis by targeting a GLUT‑1/ALDOA/PKM2 axis in esophageal carcinoma

Qu,

Xue,

Zheng

et al. 2023

Oncol Lett

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Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy of the digestive system with increasing incidence and mortality rates. The biological roles of microRNA (miR)-378a-3p in tumor cells remain contested, and the mechanisms underlying the functions, energy metabolism, and cell survival mechanisms in ESCC cells are yet to be fully elucidated. In the present study, miR-378a-3p overexpression and negative control plasmids were transfected into ECA-109 cells using electroporation. Western blotting was used to detect the relative expression of proteins, and flow cytometry was used to detect cell apoptosis. Subsequently, ELISA assays were performed to determine enzyme activity, and an ATP detection kit was used to measure ATP content. Dual-luciferase reporter assays were performed to identify the target genes of miR-378a-3p. The results of the present study demonstrated that miR-378a-3p inhibited the gene expression and enzyme activities of glucose transporter protein 1 (GLUT-1), Aldolase A (ALDOA), and pyruvate kinase M2 (PKM2), all of which are involved in the glycolytic pathway of cells. Energy metabolism was suppressed by miR-378a-3p by reducing ATP content, and this downregulated the expression of Bcl-2 and Survivin.Moreover, increased miR-378a-3p expression promoted cell apoptosis in the early stages by increasing the expression levels and the activity of Bad and Caspase-3, while inhibiting the expression levels of Bcl-2 and Survivin. The results of the present study also demonstrated that GLUT-1/ALDOA/PKM2 were target genes of miR-378a-3p. Notably, miR-378a-3p blocked energy production and promoted the apoptosis of tumor cells via the downregulation of glycolytic enzyme expression and by reducing the mitochondrial membrane potential in ESCC. Bad, Caspase-3, Survivin, and Bcl-2 may be associated with blocking energy production and promoting apoptosis via miR-378a-3p in ESCC cells.

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“…Although the pharmacological benefits of glucocorticoids are significant, it is important that clinicians be aware that glucocorticoids might directly affect the phenotype in various types of solid tumors, including breast cancer, 9 ovarian cancer, 10 lung cancer, 11 and pancreatic cancer. [12][13][14][15] In the present study, we used RNA sequencing (RNA-seq) to examine the changes in molecular expressions induced by DEX treatment of PDAC cells. We report that two highly induced molecules, KRT6A and ECM1, are involved in the progression of PDAC.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ECM1 and KRT6A are involved in tumor progression and chemoresistance in the effect of dexamethasone on pancreatic cancer

Shinomiya,

Kouchi,

Harada‐Kagitani

et al. 2024

Cancer Science

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Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis. Neoadjuvant chemotherapy is an effective PDAC treatment option, but chemotherapy causes unfavorable side effects. Glucocorticoids (e.g., dexamethasone [DEX]) are administered to reduce side effects of chemotherapy for solid tumors, including pancreatic cancer. Glucocorticoids have both beneficial and detrimental effects, however. We investigated the functional changes and gene‐expression profile alterations induced by DEX in PDAC cells. PDAC cells were treated with DEX, and the cell proliferation, migration, invasion, and chemosensitivity to gemcitabine (GEM) were evaluated. The results demonstrated decreased cell proliferative capacity, increased cell migration and invasion, and decreased sensitivity to GEM. A comprehensive genetic analysis revealed marked increases in ECM1 and KRT6A in DEX‐treated PDAC cells. We evaluated the effects of ECM1 and KRT6A expression by using PDAC cells transfected with those genes. Neither ECM1 nor KRT6A changed the cells’ proliferation, but each enhanced cell migration and invasion. ECM1 decreased sensitivity to GEM. We also assessed the clinicopathological significance of the expressions of ECM1 and KRT6A in 130 cases of PDAC. An immunohistochemical analysis showed that KRT6A expression dominated the poorly differentiated areas. High expressions of these two proteins in PDAC were associated with a poorer prognosis. Our results thus demonstrated that DEX treatment changed PDAC cells’ functions, resulting in decreased cell proliferation, increased cell migration and invasion, and decreased sensitivity to GEM. The molecular mechanisms of these changes involve ECM1 and KRT6A, whose expressions are induced by DEX.

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Glucocorticoid-induced microRNA-378 signaling mediates the progression of pancreatic cancer by enhancing autophagy

Cited by 12 publications

References 64 publications

Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium‐Betulin Immune Agonist

Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium‐Betulin Immune Agonist

Upregulated miR‑378a‑3p expression suppresses energy metabolism and promotes apoptosis by targeting a GLUT‑1/ALDOA/PKM2 axis in esophageal carcinoma

ECM1 and KRT6A are involved in tumor progression and chemoresistance in the effect of dexamethasone on pancreatic cancer

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