Correction to: Elafin promotes tumour metastasis and attenuates the anti-metastatic effects of erlotinib via binding to EGFR in hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Wang C
PROVIDER: S-EPMC8932148 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
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Correction to: Elafin promotes tumour metastasis and attenuates the anti-metastatic effects of erlotinib via binding to EGFR in hepatocellular carcinoma.
Wang Chenwei C Liao Yadi Y He Wei W Zhang Hong H Zuo Dinglan D Liu Wenwu W Yang Zhiwen Z Qiu Jiliang J Yuan Yichuan Y Li Kai K Zhang Yuanping Y Wang Yongjin Y Shi Yunxing Y Qiu Yuxiong Y Gao Song S Yuan Yunfei Y Li Binkui B
Journal of experimental & clinical cancer research : CR 20220318 1
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Project description:BackgroundElafin is a serine protease inhibitor critical for host defence. We previously reported that Elafin was associated with the recurrence of early-stage hepatocellular carcinoma (HCC) after surgery. However, the exact role of Elafin in HCC remains obscure.MethodsHCC tissue microarrays were used to investigate the correlation between Elafin expression and the prognosis of HCC patients. In vitro migration, invasion and wound healing assays and in vivo lung metastasis models were used to determine the role of Elafin in HCC metastasis. Mass spectrometry, co-immunoprecipitation, western blotting, and immunofluorescence staining assays were performed to uncover the mechanism of Elafin in HCC. Dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the transcriptional regulation of Elafin.ResultsElafin expression was frequently increased in HCC tissues compared to normal tissues, and high Elafin expression in HCC tissues was correlated with aggressive tumour phenotypes and a poor prognosis in HCC patients. Elafin dramatically enhanced the metastasis of HCC cells both in vitro and in vivo by interacting with EGFR and activating EGFR/AKT signalling. Moreover, Elafin attenuated the suppressive effects of erlotinib on HCC metastasis. Besides, Elafin was transcriptionally regulated by Sp1 in HCC cells. Clinically, Elafin expression was positively correlated with Sp1, Vimentin, and EGFR signalling in both our HCC tissue microarrays and TCGA database analysis.ConclusionsUpregulation of Elafin by Sp1 enhanced HCC metastasis via EGFR/AKT pathway, and overexpression of Elafin attenuated the anti-metastatic effects of erlotinib, suggesting a valuable prognostic biomarker and therapeutic target for HCC.
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Project description:Supplementary Table 1 and the Supplementary Figure legends were not included when this manuscript was first published. The files are now available here.
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Project description:Background & aimsCancer metastasis is responsible for the majority of cancer-related deaths. Exosomal miRNAs have emerged as promising biomarkers for cancer, serving as signaling molecules that can regulate tumor growth and metastasis. This study examined circulating exosomal miRNAs that could predict hepatocellular carcinoma (HCC) metastasis.MethodsExosomal miRNA was measured by quantitative real-time PCR (qRT-PCR) in a large set of patients (n = 284). To investigate the role of exosomal miRNA in HCC, we performed a series of in vitro tests, such as exosome labeling, qRT-PCR, reverse transcription PCR, wound healing assay, transwell assay, and Western blot assay.ResultsExosomal miR-125b was drastically downregulated in HCC patients with metastasis than in those without metastasis. In vitro, we observed the uptake of miR-125b by exosome in recipient cells. Exosome-mediated miR-125b significantly inhibited migration and invasion abilities and downregulated the mRNA expressions of MMP-2, MMP-9, and MMP-14 in recipient cells via intercellular communication. Further investigation revealed that miR-125b suppressed SMAD2 protein expression in recipient cells by binding to its 3' untranslated regions. Exosome-mediated miR-125b transfer also disrupted TGF-β1-induced epithelial-mesenchymal transition and TGF-β1/SMAD signaling pathway in recipient cells by leading to a decrease of SMAD2 protein expression. Moreover, exosomal miR-125b was downregulated after metastasis compared with that at baseline in patients with serial measurements before and after metastasis.ConclusionsThe results imply that exosome-mediated miR-125b exerts anti-metastatic properties in HCC. These findings highlight that circulating exosomal miR-125b might represent a reliable biomarker with diagnostic and therapeutic implications for extrahepatic metastasis from HCC.
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Project description:IntroductionThe phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46-0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan.MethodsPatients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing.ResultsThe Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431-0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424-1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317-0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients).ConclusionsClinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.
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Project description:Nasopharyngeal carcinoma (NPC) is the most common cancer with high metastatic potential that occurs in the epithelial cells of the nasopharynx. Distant metastases are the primary cause for treatment failure and mortality of NPC patients. However, the underlying mechanism responsible for the initiation of tumour cell dissemination and tumour metastasis in NPC is not well understood. Here, we demonstrated that epidermal growth factor receptor (EGFR) was highly expressed in tumour tissues of NPC patients with distant metastases and was associated with a decrease in reactive oxygen species (ROS). We also revealed that extracellular vesicles (EVs) transfer occurred from highly to poorly metastatic NPC cells, mediating cell-cell communication and enhancing the metastatic potential of poorly metastatic NPC cells. Further experiments indicated that EVs derived from highly metastatic NPC cells induced the up-regulation of EGFR and down-regulation of ROS in low metastatic NPC cells. Mechanistically, EGFR-rich EVs-mediated EGFR overexpression down-regulated intracellular ROS levels through the PI3K/AKT pathway, thus promoting the metastatic potential of poorly metastatic NPC cells. Strikingly, treatment with EVs secreted from highly metastatic NPC cells was significantly associated with rapid NPC progression and shorter survival in xenografted mice. These findings not only improve our understanding of EVs-mediated NPC metastatic mechanism but also have important implications for the detection and treatment of NPC patients accompanied by aberrant EGFR-rich EVs transmission.
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Project description:PurposeIn RELAY, ramucirumab plus erlotinib (RAM + ERL) improved progression-free survival (PFS) in patients with untreated, metastatic, EGFR-mutated, non-small cell lung cancer (NSCLC). Here, we present the exposure-response relationship of RAM from RELAY.MethodsPatients received ERL (150 mg/day) with either RAM (10 mg/kg) or placebo (PBO + ERL) every 2 weeks (Q2W). A population pharmacokinetic model predicted RAM minimum concentration after first dose (Cmin,1), and at steady state (Cmin,ss), which were used to evaluate correlation between RAM exposure and efficacy and safety. The Kaplan-Meier method and Cox regression analyses were utilized to evaluate exposure-efficacy by Cmin,1 quartile. Exposure-safety was evaluated by assessing incidence rates for safety parameters by Cmin,ss quartile, with ordered categorical analysis used for ALT/AST only.ResultsAnalyses included 216 patients treated with RAM + ERL and 225 patients treated with PBO + ERL. Adjusting for significant baseline covariates, no exposure-efficacy relationship was identified in RELAY: PFS hazard ratio (mean, 95% confidence intervals) for the Cmin,1 quartiles were 0.67 (0.45-0.99), 0.77 (0.53-1.12), 0.57 (0.38-0.84), and 0.50 (0.33-0.76). No apparent exposure-safety relationship was observed for selected safety endpoints, including Grade ≥ 3 hypertension, diarrhea, and dermatitis acneiform, and any grade hypertension, any grade and Grade ≥ 3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury.ConclusionsNo association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC.Trial registrationClinicalTrials.gov, NCT02411448.
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Project description:Colorectal cancer remains one of the most common causes of cancer diagnoses and mortality in the United States. The treatment of metastatic colorectal cancer has evolved significantly over the last decade with near-tripling of patient survival rate. A significant contribution to this outcome was the advent of novel targeted agents, such as the epidermal growth factor (EGFR) inhibitors. In an era of emphasis on refining therapy, the presence of KRAS mutation will predict for resistance and limit exposure to patients who are more likely to benefit. In contrast, the presence of BRAF mutations does not seem to have a predictive value. Agents that are thought to reverse resistance to EGFR inhibitors such as those targeting PI3K, c-MET or IGF-1R are currently under study. EGFR inhibitors have exhibited single agent activity, and seem to synergize very well with standard chemotherapy except for cetuximab and 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX). Preliminary data suggests that EGFR inhibitors have similar effectiveness to vascular endothelial growth factor (VEGF) inhibitors in the first line setting. Skin toxicity remains the main limiting factor for the utilization of EGFR inhibitors, but strategies including the use of agents such as minocycline or doxycycline added to topical care seem to limit the severity of the rash.
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Project description:[This corrects the article DOI: 10.18632/oncotarget.13687.].
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