Fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m
A) demethylase, participates in tumor progression and metastasis in many malignancies, but its role in colorectal cancer (CRC) ...is still unclear. Here, we found that FTO protein levels, but not RNA levels, were downregulated in CRC tissues. Reduced FTO protein expression was correlated with a high recurrence rate and poor prognosis in resectable CRC patients. Moreover, we demonstrated that hypoxia restrained FTO protein expression, mainly due to an increase in ubiquitin-mediated protein degradation. The serine/threonine kinase receptor associated protein (STRAP) might served as the E3 ligase and K216 was the major ubiquitination site responsible for hypoxia-induced FTO degradation. FTO inhibited CRC metastasis both in vitro and in vivo. Mechanistically, FTO exerted a tumor suppressive role by inhibiting metastasis-associated protein 1 (MTA1) expression in an m
A-dependent manner. Methylated MTA1 transcripts were recognized by an m
A "reader", insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which then stabilized its mRNA. Together, our findings highlight the critical role of FTO in CRC metastasis and reveal a novel epigenetic mechanism by which the hypoxic tumor microenvironment promotes CRC metastasis.
As one of the world’s most populous countries, China bears a heavy burden and a broad spectrum of cancers, including unique types, providing a unique environment for drug research and development. In ...recent years, China has leapt forward in oncology drug development and clinical trials, presenting new opportunities and challenges.
As one of the world’s most populous countries, China bears a heavy burden and a broad spectrum of cancers, including unique types, providing a unique environment for drug research and development. In recent years, China has leapt forward in oncology drug development and clinical trials, presenting new opportunities and challenges.
In recent years, remarkable breakthroughs have been reported on antibody‐drug conjugates (ADCs), with 15 ADCs successfully entering the market over the past decade. This substantial development has ...positioned ADCs as one of the fastest‐growing domains in the realm of anticancer drugs, demonstrating their efficacy in treating a wide array of malignancies. Nonetheless, there is still an unmet clinical need for wider application, better efficacy, and fewer side effects of ADCs. An ADC generally comprises an antibody, a linker and a payload, and the combination has profound effects on drug structure, pharmacokinetic profile and efficacy. Hence, optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects. In this review, we comprehensively reviewed the current development and the prospects of ADC, provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China, highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies, and also discussed the new related technologies, possibility of next‐generation ADCs and the directions of clinical research.
Summary
A recent study indicated that Lectin‐type oxidized LDL receptor‐1 (LOX‐1) was a distinct surface marker for human polymorphisms myeloid‐derived suppressor cells (PMN‐MDSC). The present study ...was aimed to investigate the existence LOX‐1 PMN‐MDSC in hepatocellular carcinoma (HCC) patients. One hundred and twenty‐seven HCC patients, 10 patients with mild active chronic hepatitis B, 10 liver cirrhosis due to hepatitis B, 10 liver dysplastic node with hepatitis B and 50 health control were included. LOX‐1+ CD15+ PMN‐MDSC were significantly elevated in HCC patients compared with healthy control and patients with benign diseases. LOX‐1+ CD15+ PMN‐MDSC in circulation were positively associated with those in HCC tissues. LOX‐1+ CD15+ PMN‐MDSCs significantly reduced proliferation and IFN‐γ production of T cells with a dosage dependent manner with LOX‐1− CD15+ PMNs reached negative results. The suppression on T cell proliferation and IFN‐γ production was reversed by ROS inhibitor and Arginase inhibitor. ROS level and activity of arginase of LOX‐1 +CD15+ PMN were higher in LOX‐1+ CD15+ PMN‐MDSCs than LOX‐1− CD15+ PMNs, as well as the expression of the NADPH oxidase NOX2 and arginase I. RNA sequence revealed that LOX‐1+ CD15+ PMN‐MDSCs displayed significantly higher expression of spliced X‐box ‐binding protein 1 (sXBP1), an endoplasmic reticulum (ER) stress marker. ER stress inducer induced LOX‐1 expression and suppressive function for CD15+ PMN from health donor. For HCC patients, LOX‐1+ CD15+ PMN‐MDSCs were positively related to overall survival. Above all, LOX‐1+ CD15+ PMN‐MDSC were elevated in HCC patients and suppressed T cell proliferation through ROS/Arg I pathway induced by ER stress. They presented positive association with the prognosis of HCC patients.
A recent study indicated that lectin‐type oxidized LDL receptor‐1 (LOX‐1) was a distinct surface marker for human polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSC). The present study found that LOX‐1+ CD15+ PMN‐MDSC were elevated in hepatocellular carcinoma (HCC) patients and suppressed T‐cell proliferation through ROS/Arg I pathway induced by ER stress. They presented a positive association with the prognosis of HCC patients.
Growing evidence implies a link between DNA methylation and tumor immunity/immunotherapy. However, the global influence of DNA methylation on the characteristics of the tumor microenvironment and the ...efficacy of immunotherapy remains to be clarified. In this study, we systematically evaluated the DNA methylation regulator patterns and tumor microenvironment characteristics of 1,619 gastric cancer patients by clustering the gene expression of 20 DNA methylation regulators. Three gastric cancer subtypes that had different DNA methylation modification patterns and distinct tumor microenvironment characteristics were recognized. Then, a DNA methylation score (DMS) was constructed to evaluate DNA methylation modification individually. High DMS was characterized by immune activation status, increased tumor mutation burden, and tumor neoantigens, with a favorable prognosis. Conversely, activation of the stroma and absence of immune cell infiltration were observed in the low DMS group, with relatively poor survival. High DMS was also certified to be correlated with enhanced efficacy of immunotherapy in four immune checkpoint blocking treatment cohorts. In conclusion, the characterization of DNA methylation modification patterns may help to enhance our recognition of the tumor immune microenvironment of gastric cancer and guide more personalized immunotherapy strategies in the future.
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Qiu and colleagues identified three distinct immune subtypes in GC from the perspective of DNA methylation and constructed an individual DNA methylation score (DMS). DMS is a valuable tool for the prediction of survival, clinicopathological characteristics, and the efficacy of immunotherapy and might guide more personalized immunotherapy strategies.
AIM: To investigate the prognostic value of preoperative lymphocyte-to-monocyte ratio(LMR) in patients with hepatocellular carcinoma(HCC) undergoing curative hepatectomy.METHODS: Clinicopathological ...data of 210 hepatitis B virus(HBV)-associated HCC patients who were treated by radical hepatic resection between 2003 and 2010 were retrospectively analyzed. None of the patients received any preoperative anticancer therapyor intraoperative radiofrequency ablation. The diagnosis was confirmed by pathological examination after surgery. Absolute peripheral blood lymphocyte and monocyte counts were derived from serum complete blood cell count before surgery,and LMR was calculated by dividing lymphocyte count by monocyte count. The best cutoff was determined by receiver operating characteristics(ROC) curve analysis. Correlations between LMR levels and clinicopathological features were assessed using the χ2 test. Survival outcomes were estimated using the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate analyses were performed to evaluate the prognostic impact of LMR and other clinicopathological factors on overall survival(OS) and recurrence-free survival(RFS),using the Cox proportional hazards model.RESULTS: The optimal cutoff value of LMR for survival analysis was 3.23,which resulted in the most appropriate sensitivity of 55.3% and specificity of 74.7%,with the area under the curve(AUC) of 0.66(95%CI: 0.593-0.725). All patients were dichotomized into either a low(≤ 3.23) LMR group(n = 66) or a high(> 3.23) LMR group(n = 144). A low preoperative LMR level was significantly correlated with the presence of cirrhosis,elevated levels of total bilirubin and larger tumor size. Patients with a low LMR level had significantly reduced 5-year OS(61.9% vs 83.2%,P < 0.001) and RFS(27.8% vs 47.6%,P = 0.009) compared to those with a high LMR level. Multivariate analyses indicated that a lower LMR level was a significantly independent predictor of inferior OS(P = 0.003) and RFS(P = 0.006). Subgroup analysis indicated that survival outcome was significantly more favorable in cirrhotic patients with LMR > 3.23. However,there were no differences between low and high LMR groups for OS and RFS in non-cirrhotic patients.CONCLUSION: Preoperative LMR was demonstrated for the first time to serve as an independent prognostic factor in HBV-associated HCC patients after curative resection. Prospective studies with larger cohorts for validation are warranted.
Background
Epstein‒Barr virus‐associated gastric cancer (EBVaGC) is regarded as a distinct molecular subtype of GC, accounting for approximately 9% of all GC cases. Clinically, EBVaGC patients are ...found to have a significantly lower frequency of lymph node metastasis and better prognosis than uninfected individuals. RNA N6‐methyladenosine (m6A) modification has an indispensable role in modulating tumour progression in various cancer types. However, its impact on EBVaGC remains unclear.
Methods
Methylated RNA immunoprecipitation sequencing (MeRIP‐seq) and m6A dot blot were conducted to compare the m6A modification levels between EBVaGC and EBV‐negative GC (EBVnGC) cells. Western blot, real‐time quantitative PCR (RT‐qPCR) and immunohistochemistry were applied to explore the underlying mechanism of the reduced m6A modification in EBVaGC. The biological function of fat mass and obesity‐associated protein (FTO) was determined in vivo and in vitro. The target genes of FTO were screened by MeRIP‐seq, RT‐qPCR and Western blot. The m6A binding proteins of target genes were verified by RNA pulldown and RNA immunoprecipitation assays. Chromatin immunoprecipitation and Luciferase report assays were performed to investigate the mechanism how EBV up‐regulated FTO expression.
Results
M6A demethylase FTO was notably increased in EBVaGC, leading to a reduction in m6A modification, and higher FTO expression was associated with better clinical outcomes. Furthermore, FTO depressed EBVaGC cell metastasis and aggressiveness by reducing the expression of target gene AP‐1 transcription factor subunit (FOS). Methylated FOS mRNA was specifically recognized by the m6A ‘reader’ insulin‐like growth factor 2 mRNA binding protein 1/2 (IGF2BP1/2), which enhanced its transcripts stability. Moreover, MYC activated by EBV in EBVaGC elevated FTO expression by binding to a specific region of the FTO promoter.
Conclusions
Mechanistically, our work uncovered a crucial suppressive role of FTO in EBVaGC metastasis and invasiveness via an m6A‐FOS‐IGF2BP1/2‐dependent manner, suggesting a promising biomarker panel for GC metastatic prediction and therapy.
FTO elevation in Epstein‒Barr virus‐associated GC contributes to favourable prognosis in patients.
FTO restrains tumour metastasis and aggressiveness in EBVaGC by down‐regulating FOS in an m6A‐dependent manner.
The m6A readers IGF2BP1/2 bind FOS nascent transcripts and maintain FOS mRNA stability.
Targeting the FTO⊣FOS/ IGF2BP1/2 axis renders a promising strategy for GC therapy.
AIM: To evaluate the impact of postoperative infectious complications on hepatocellular carcinoma following curative hepatectomy.METHODS:We performed a retrospective analysis of200 hepatocellular ...carcinoma patients who underwent hepatectomy at our institution between September2003 and June 2011.The patients’demographics,clinicopathological characteristics and postoperative infectious complications were analyzed.The ClavienDindo classification was adopted to assess the severity of complications.The dynamic change in the neutrophilto-lymphocyte ratio,defined as the absolute neutrophil count divided by the absolute lymphocyte count,after surgery was also investigated.The observation endpoints for this study were recurrence-free survival and overall survival of the patients.Statistical analysis of the survival curves was performed using the KaplanMeier method and the log-rank test.The prognosticvalue of each variable for predicting prognosis was assessed via multivariate Cox proportional hazards regression analysis.The cutoff score for each variable was selected based on receiver operating characteristic curve analysis.All statistical tests were two-sided,and significance was set at P<0.05.RESULTS:The median age of the patients was 49years,and the majority of patients were male(86%)and had been infected with hepatitis B virus(86%).The 30-d postoperative infectious complication rate was34.0%(n=68).Kaplan-Meier survival analysis revealed that postoperative infection was significantly correlated with tumor recurrence(P<0.001).The postoperative intra-abdominal infection group exhibited a worse prognosis than the non-intra-abdominal infection group(P<0.001).A significantly increased incidence of postoperative intra-abdominal infection was observed in the patients with hepatic cirrhosis(P=0.028),concomitant splenectomy(P=0.007)or vascular invasion(P=0.026).The patients who had an elevated postoperative neutrophil-to-lymphocyte ratio change(>1.643)clearly exhibited poorer recurrence-free survival than those who did not(P=0.009),although no significant correlation was observed between overall survival and the change in the postoperative neutrophilto-lymphocyte ratio.Based on multivariate analysis,hepatitis B surface antigen positivity,Child-TurcottePugh class B,an elevated postoperative neutrophilto-lymphocyte ratio change and intra-abdominal infection were significant predictors of poor recurrencefree survival.Hepatic cirrhosis,the maximal tumor diameter and intra-abdominal infection were significant predictors of overall survival.CONCLUSION:Postoperative intra-abdominal infection adversely affected oncologic outcomes,and the change in postoperative neutrophil-to-lymphocyte ratio was a good indicator of tumor recurrence in hepatocellular carcinoma patients after curative hepatectomy.
Abstract Purpose Here, we evaluate the prognostic effect of pretreatment serum lactate dehydrogenase (LDH) in locally advanced nasopharyngeal carcinoma (NPC). Methods and materials Pretreatment serum ...samples from a randomized controlled trial, which contained 199 neoadjuvant chemoradiotherapy patients and 201 neoadjuvant-concurrent chemoradiotherapy cases with locally advanced NPC, were collected and examined for LDH. With 5-year follow-up, the prognostic effect of pretreatment serum LDH was analysed by Kaplan–Meier analysis and multivariate Cox regression model. Results Three hundred and sixty-seven patients (91.75%) had a normal (109.0–245.0 U/L) pretreatment LDH level, compared to 33 cases (8.25%) that had a higher (⩾245.0 U/L) LDH level. The mean and median pretreatment LDH levels of these 400 patients were 186.6 and 174.0 U/L (range, 83.0–751.0 U/L), respectively. Compared with the normal subset, elevated LDH level predicted an inferior 5-year overall survival (56.9% versus 76.8%, P = 0.004), disease-free survival (DFS, 45.4% versus 64.7%, P = 0.001), local relapse-free survival (76.1% versus 89.6%, P = 0.019) and distant metastasis-free survival (DMFS, 54.3% versus 72.2%, P = 0.001). Multivariate analysis confirmed that the LDH level was an independent prognostic factor to predict death, disease progression, local relapse and distant metastasis. For the subgroup with normal LDH (median point of 177.0 U/L), we detected an evident 5-year DFS (68.8% versus 59.5%, P = 0.047) and DMFS advantage (77.3% versus 65.3%, P = 0.016) in 109.0–177.0 U/L subset than that of 178.0–245.0 U/L subgroup. Conclusions Serological LDH level was an independent prognostic factor for locally advanced NPC. Combining pretreatment LDH with TNM staging might lead to more accurate risk definition.
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