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The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis. Leukemia inhibitory factor receptor (LIFR) is frequently downregulated in liver cancer. Here the authors show that loss of LIFR promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis through NF-κB-mediated upregulation of iron-sequestering cytokine LCN2.

During early pregnancy in mice, leukemia inhibitory factor (LIF) regulates embryo implantation by activating the JAK/STAT3 signaling pathway. The STAT3 pathway has been recognized to play a critical role in embryo implantation; however, it remains unclear whether STAT3 activation alone is sufficient to induce implantation. In this study, we investigated the effects of RO8191, a potential STAT3 activator, on embryo implantation through a series of studies with different mouse models. We found that RO8191 can induce embryo implantation and decidual reaction by activating STAT3, but not STAT1, signaling in both epithelial and stromal compartments in delayed implantation models. Furthermore, RO8191 was able to rescue implantation and establish pregnancy even in uterine epithelial-specific Lifr conditional knockout (cKO) mice, which exhibit infertility due to implantation failure. In contrast, in uterine epithelial-specific Stat3 or Gp130 conditional knockout (cKO) mice, which also show embryo implantation failure, RO8191 induces only a partial decidual response. These results suggest that STAT3, Gp130 and LIFR each play distinct roles in embryo implantation and development. Although the detailed mechanisms underlying RO8191’s action remain to be elucidated, our findings provide insights supporting its potential application in treating recurrent implantation failure.

In recent years, circular RNAs (circRNAs) have been revealed to have important roles in carcinogenesis. Metastasis is the leading cause of lung adenocarcinoma (LUAC) death. However, the contributions of circRNA to the metastasis of LUAC remain largely unknown. Based on circBase data and our biobank tissues, we identified circCRIM1 (a circRNA derived from exons 2, 3 and 4 of the CRIM1 gene, hsa_circ_0002346) as having a significantly decreased expression in LUAC samples compared with matched normal control samples. Both in vivo and in vitro experiments revealed that circCRIM1 suppresses the invasion and metastasis of LUAC. In vitro precipitation of circRNAs, luciferase reporter assay, and biotin‐coupled microRNA capture were carried out to investigate the Ago2‐dependent interaction of circCRIM1 and microRNA (miR)‐93/miR‐182. Mechanistically, we found that circCRIM1 could promote the expression of leukemia inhibitory factor receptor, a well‐known tumor suppressor, by sponging miR‐93 and miR‐182. In the clinical and pathological analyses, the downregulation of circCRIM1 in LUAC was significantly correlated with lymphatic metastasis and TNM stage, which served as an independent risk factor for the overall survival of patients with LUAC. Our study showed that circCRIM1 inhibits the invasion and metastasis of lung adenocarcinoma cancer cells, which makes it a potential therapeutic target. Upregulation of circCRIM1 exerts the invasion‐suppression effect dependent on the circCRIM1‐microRNA‐182/93‐leukemia inhibitory factor receptor axis.

FAM3C/ I nterleukin- l ike E MT I nducer (ILEI) is an oncogenic member of the FAM3 cytokine family and serves essential roles in both epithelial-mesenchymal transition (EMT) and breast cancer metastasis. ILEI expression levels are regulated through a non-canonical TGFβ signaling pathway by 3′-UTR-mediated translational silencing at the mRNA level by hnRNP E1. TGFβ stimulation or silencing of hnRNP E1 increases ILEI translation and induces an EMT program that correlates with enhanced invasion and migration. Recently, EMT has been linked to the formation of breast cancer stem cells (BCSCs) that confer both tumor cell heterogeneity as well as chemoresistant properties. Herein, we demonstrate that hnRNP E1 knockdown significantly shifts normal mammary epithelial cells to mesenchymal BCSCs in vitro and in vivo. We further validate that modulating ILEI protein levels results in the abrogation of these phenotypes, promoting further investigation into the unknown mechanism of ILEI signaling that drives tumor progression. We identify LIFR as the receptor for ILEI, which mediates signaling through STAT3 to drive both EMT and BCSC formation. Reduction of either ILEI or LIFR protein levels results in reduced tumor growth, fewer tumor initiating cells and reduced metastasis within the hnRNP E1 knock-down cell populations in vivo. These results reveal a novel ligand-receptor complex that drives the formation of BCSCs and represents a unique target for the development of metastatic breast cancer therapies.

Despite advances in breast cancer treatment, residual disease driven by dormant tumor cells continues to be a significant clinical problem. Leukemia inhibitory factor receptor (LIFR) promotes a dormancy phenotype in breast cancer cells and LIFR loss is correlated with poor patient survival. Herein, we demonstrate that histone deacetylase inhibitors (HDACi), which are in phase III clinical trials for breast cancer, epigenetically induced LIFR and activated a pro-dormancy program in breast cancer cells. HDACi slowed breast cancer cell proliferation and reduced primary tumor growth. Primary breast tumors from HDACi-treated patients had increased LIFR levels and reduced proliferation rates compared to pre-treatment levels. Recent Phase II clinical trial data studying entinostat and azacitidine in metastatic breast cancer revealed that induction of several pro-dormancy genes post-treatment was associated with prolonged patient survival. Together, these findings suggest HDACi as a potential therapeutic avenue to promote dormancy, prevent recurrence, and improve patient outcomes in breast cancer.

Adequate differentiation or decidualization of endometrial stromal cells (ESC) is critical for successful pregnancy in humans and rodents. Here, we investigated the role of leukemia inhibitory factor (LIF) in human and murine decidualization. Ex vivo human (H) ESC decidualization was induced by estrogen (E, 10(-8) M) plus medroxyprogesterone acetate (MPA, 10(-7) M). Exogenous LIF (≥50 ng/ml) induced STAT3 phosphorylation in non-decidualized and decidualized HESC and enhanced E+MPA-induced decidualization (measured by PRL secretion, P<0.05). LIF mRNA in HESC was down-regulated by decidualization treatment (E+MPA) whereas LIF receptor (R) mRNA was up-regulated, suggesting that the decidualization stimulus 'primed' HESC for LIF action, but that factors not present in our in vitro model were required to induce LIF expression. Ex vivo first trimester decidual biopsies secreted >100 pg/mg G-CSF, IL6, IL8, and MCP1. Decidualized HESC secreted IL6, IL8, IL15 and MCP1. LIF (50 ng/ml) up-regulated IL6 and IL15 (P<0.05) secretion in decidualized HESC compared to 0.5 ng/ml LIF. In murine endometrium, LIF and LIFR immunolocalized to decidualized stromal cells on day 5 of gestation (day 0 = day of plug detection). Western blotting confirmed that LIF and the LIFR were up-regulated in intra-implantation sites compared to inter-implantation sites on Day 5 of gestation. To determine the role of LIF during in vivo murine decidualization, intra-peritoneal injections of a long-acting LIF antagonist (PEGLA; 900 or 1200 µg) were given just post-attachment, during the initiation of decidualization on day 4. PEGLA treatment reduced implantation site decidual area (P<0.05) and desmin staining immuno-intensity (P<0.05) compared to control on day 6 of gestation. This study demonstrated that LIF was an important regulator of decidualization in humans and mice and data provides insight into the processes underlying decidualization, which are important for understanding implantation and placentation.

Trastuzumab‐emtansine (T‐DM1) is an antibody‐drug conjugate that has been approved for the treatment of human epidermal growth factor receptor 2 (HER2)‐positive metastatic breast cancer. Despite the remarkable efficacy of T‐DM1 in many patients, resistance to this therapeutic has emerged as a significant clinical problem. In the current study, we used BT‐474/KR cells, a T‐DM1‐resistant cell line established from HER2‐positive BT‐474 breast cancer cells, as a model to investigate mechanisms of T‐DM1 resistance and explore effective therapeutic regimens. We show here for the first time that activation of signal transducer and activator of transcription 3 (STAT3) mediated by leukemia inhibitory factor receptor (LIFR) overexpression confers resistance to T‐DM1. Moreover, secreted factors induced by activated STAT3 in resistant cells limit the responsiveness of cells that were originally sensitive to T‐DM1. Importantly, STAT3 inhibition sensitizes resistant cells to T‐DM1, both in vitro and in vivo, suggesting that the combination T‐DM1 with STAT3‐targeted therapy is a potential treatment for T‐DM1‐refractory patients. We show for the first time that activated STAT3 mediated by LIFR overexpression confers resistance to T‐DM1. Notably, secreted factors induced by activated STAT3 in resistant cells limited responses to T‐DM1 in originally sensitive cells. The resistance to T‐DM1 could be overcome by napabucasin, a STAT3 inhibitor, both in vitro and in vivo.

Neuroendocrine (NE) differentiation is a well-recognized phenotypic change of prostate cancer after androgen deprivation therapy (ADT), and it ultimately develops into an aggressive subset of this disease. However, the contribution of signaling pathways that lead to metabolic disorders and NE differentiation of prostate cancer remains unclear. In this study, we identified that ADT induced upregulation of the succinate-CoA ligase GDP-forming beta subunit (SUCLG2), which regulates succinate metabolism and NE differentiation of prostate cancer. We demonstrated a connection that upregulation of epidermal growth factor receptor (EGFR)-leukemia inhibitory factor receptor (LIFR) signaling induced SUCLG2 expression in prostate cancer cells. The LIFR is upregulated by nuclear EGFR, which acts as a transcriptional regulator, directly binds to the LIFR promoter, and drives NE differentiation and glycolysis of prostate cancer. LIFR upregulation is associated with SUCLG2, which increased succinate synthesis and enzymatic activities of mitochondrial nucleoside diphosphate kinase (NDPK) in prostate cancer cells. Knockdown of SUCLG2 suppressed NE differentiation in cultured cells and reduced prostate tumor growth in a xenograft model. Analysis of prostate tissue samples showed increased intensity of nuclear EGFR associated with the LIFR and SUCLG2 in castration-resistant prostate cancer tumors. Our study provides a mechanism whereby ADT upregulates EGFR–LIFR signaling that activates SUCLG2, which subsequently stimulates the metabolic changes associated with NE differentiation and aggressive prostate cancer phenotype.

Oral squamous cell carcinoma (OSCC) is an aggressive cancer with 60% survival rate, high mortality, and morbidity. Leukaemia inhibitory factor (LIF) and its receptor (LIF-R) are involved in the activation of the signal transducer and activator of transcription-3 (STAT3) pathway which has central involvement in the signalling pathways involved in important pathological processes including carcinogenesis and inflammation. STAT3 and its activators have shown prognostic significance in OSCC. The aim is to evaluate the immunohistochemical (IHC) expression of LIF and LIF-R proteins in OSCC. Four tissue microarrays (TMA) including OSCC ( n  = 95) and normal oral mucosa (NOM; n  = 11) as control tissue were used in this study. FIJI software was for semi-quantitative analysis of IHC expression of LIF and LIF-R. Statistical analysis were performed using SPSS. LIF-R was expressed to a significantly higher extent in OSCC compared to NOM ( p  = 0.02) and LIF was expressed to a significantly higher extent in NOM compared to OSCC ( p  < 0.001) and in the buccal mucosa compared to the gingiva/alveolar mucosa ( p  = 0.022) and the lip vermilion ( p  = 0.17). No other significant differences were found in LIF and LIF-R expression when OSCC were compared according to site, grade, or stage. This is the first study to confirm the expression of LIF in OSCC and NOM. The biphasic lower expression of LIF and higher expression of LIF-R in OSCC may indicate a key point of differentiation between NOM and OSCC. The downregulation of LIF expression may be an indication of promotion towards malignancy.

Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed. LIFR and its ligand, LIF, have been shown to play a critical role in the progression of multiple solid cancers and therapy resistance. The role of LIF/LIFR in the progression of Type II ECa, on the other hand, is unknown. We investigated the role of LIF/LIFR signaling in Type II ECa and tested the efficacy of EC359, a novel small-molecule LIFR inhibitor, against Type II ECa. The analysis of tumor databases has uncovered a correlation between diminished survival rates and increased expression of leukemia inhibitory factor (LIF), suggesting a potential connection between altered LIF expression and unfavorable overall survival in Type II ECa. The results obtained from cell viability and colony formation assays demonstrated a significant decrease in the growth of Type II ECa LIFR knockdown cells in comparison to vector control cells. Furthermore, in both primary and established Type II ECa cells, pharmacological inhibition of the LIF/LIFR axis with EC359 markedly decreased cell viability, long-term cell survival, and invasion, and promoted apoptosis. Additionally, EC359 treatment reduced the activation of pathways driven by LIF/LIFR, such as AKT, mTOR, and STAT3. Tumor progression was markedly inhibited by EC359 treatment in two different patient-derived xenograft models in vivo and patient-derived organoids ex vivo. Collectively, these results suggest LIFR inhibitor EC359 as a possible new small-molecule therapeutics for the management of Type II ECa.