Intratumoral microbiome impacts immune infiltrates in tumor microenvironment and predicts prognosis in esophageal squamous cell carcinoma patients

BackgroundDifferent intratumoral microbiotaexist in different tumors and play a crucial function in carcinogenesis. However, whether they impact clinical outcomes in esophageal squamous cell carcinoma (ESCC) and their mechanism remain unclear.Methods16S rDNA amplicon sequencing was performed on surgically resected samples from 98 ESCC patients to analyze intratumoral microbiome abundance and composition. Multiplex fluorescent immunohistochemistry staining was used to profile the phenotypes of immune infiltrates in the tumor microenvironment (TME).ResultsPatients with higher intratumoral Shannon index had significantly worse surgical outcomes. When patients were divided into short-term survivors and long-term survivors based on the median survival time, both intratumoral alpha-diversity and beta-diversity were found to be significantly inconsistent, and the relative abundance of Lactobacillus and Leptotrichia emerged as the two microorganisms that probably influenced the survival of ESCC patients. Only Lactobacillus in ESCC was validated to significantly worsen patients’ prognoses and to be positively correlated with the Shannon index. Multivariate analysis revealed that the intratumoral Shannon index, the relative abundance of Lactobacillus, and the pathologic tumor–node–metastasis (pTNM) stage were independently associated with patients’ overall survival. Furthermore, the relative abundance of both Lactobacillus and Shannon index was positively correlated with the proportions of PD-L1+ epithelial cells (ECs) and tumor-associated macrophages (TAMs). The Shannon index was negatively correlated with the proportions of natural killer (NK) cells in the TME.ConclusionsA high abundance of intratumoral Lactobacillus and bacterial alpha-diversity was associated with the formation of the immunosuppressive TME and predicted poor long-term survival in ESCC patients

Family history of cancer is a prognostic factor for better survival in operable esophageal squamous cell carcinoma: A propensity score matching analysis

Lay summaryPatients with a family history of cancer, especially digestive tract cancer and esophageal cancer, a family history of cancer in the first degree, and more than one relative affected by cancer were associated with favorable survival when compared to those without a family history of cancer.Precis for use in the Table of ContentsA family history of cancer is a favorable independent prognostic factor in ESCC. Patients with a family history of cancer, especially digestive tract cancer and esophageal cancer, a family history of cancer in the first degree, and more than one relative affected by cancer were associated with favorable survival when compared to those without a family history of cancer.BackgroundA family history of cancer (FH) is closely associated with the risk and survival of many cancers. However, the effect of FH on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains unclear. We performed a large cohort study in the Chinese population to obtain insight into the prognostic value of FH in patients with operable ESCC.MethodsA total of 1,322 consecutive patients with thoracic ESCC who had undergone esophagectomy between January 1997 and December 2013 were included. The FH group included patients with any degree of FH, while the non-FH group included patients without any degree of FH. In total, 215 patients with FH and 215 without FH were matched using the propensity score matching analysis method to adjust for differences in baseline variables between the two groups. The impact of FH on disease-free survival (DFS) and overall survival (OS) was estimated using the Kaplan–Meier method and Cox’s proportional hazards models.ResultsBefore matching, 280 (21.2%) patients were included in the FH group and 1,042 (78.8%) in the non-FH group. FH was associated with early pathological T stage (p = 0.001), lymph node-negative status (p = 0.022), and early pathological stage (p = 0.006). After matching, FH was an independent prognostic factor for DFS and OS in ESCC patients. Patients with FH had 35% lower risk of disease progression (hazard ratio [HR] = 0.65, 95% CI: 0.51–0.84, p = 0.001) and 34% lower risk of death (HR = 0.66, 95% CI: 0.51–0.86, p = 0.002) than those without FH. Patients with a family history of digestive tract cancer (FH-DC), a family history of esophageal cancer (FH-EC), FH in first-degree relatives (FH-FD), and more than one relative affected by cancer were associated with favorable DFS and OS as compared to those without FH.ConclusionFH is a favorable independent prognostic factor in ESCC. Patients with FH, especially those with FH-DC, FH-EC, FH-FD, and more than one relative affected by cancer, had improved survival

miR-424 coordinates multilayered regulation of cell cycle progression to promote esophageal squamous cell carcinoma cell proliferationResearch in context

Background: Dysregulation of the cell cycle has been implicated in esophageal squamous cell carcinoma (ESCC) progression. This study aimed to evaluate the role of miR-424 in cell cycle regulation and ESCC proliferation. Methods: The role of miR-424 in cell proliferation was evaluated in vitro and in vivo. Transcriptional activation of miR-424 was determined using chromatin immunoprecipitation, and binding of miR-424 to targets was verified using miRNA ribonucleoprotein complex immunoprecipitation. Findings: miR-424 was upregulated and correlated with poor survival in ESCC patients. Repression or overexpression of miR-424 respectively decreased or increased ESCC cell proliferation in vitro and in vivo. miR-424 expression is transcriptionally regulated by E2F1 and increased during G1/S transition. Knockdown or overexpression of miR-424 respectively inhibited or promoted both G1/S and G2/M cell cycle transitions in ESCC cells, and these effects were mediated by two newly identified miR-424 targets, PRKCD and WEE1, respectively. Consequently, elevation of PRKCD by miR-424 knockdown led to enhanced stability of the p21Cip1 protein via increased activation of PRKCD and downstream p38 MAPK and JNK signaling to block CDK2 activation and G1/S transition, while elevated WEE1 maintained CDC2 in an inactive state to block G2/M transition. However, circLARP4 could sponge the binding of miR-424 to PRKCD, thus compromising the regulation of G1/S progression by miR-424. Interpretation: miR-424 coordinates a previously unknown, multilayered regulation of ESCC cell cycle progression to promote ESCC proliferation, and may be used as a novel prognostic marker and an effective therapeutic target for ESCCs. Fund: National Natural Science Foundation of China. Keywords: miR-424, Esophageal squamous cell carcinoma, Cell cycle, Cell proliferatio

NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer

Summary: Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here, we find that the ac4C RNA acetyltransferase NAT10 is significantly upregulated in esophageal cancers (ESCAs) and associated with poor ESCA prognosis. In addition, using ESCA cell lines and mouse models, we confirm the critical functions of NAT10 in promoting ESCA tumorigenesis and progression in vitro and in vivo. Mechanistically, NAT10 depletion reduces the abundance of ac4C-modified tRNAs and decreases the translation efficiencies of mRNAs enriched for ac4C-modified tRNA-decoded codons. We further identify EGFR as a key downstream target that facilitates NAT10’s oncogenic functions. In terms of clinical significance, we demonstrate that NAT10 depletion and gefitinib treatment synergistically inhibit ESCA progression in vitro and in vivo. Our data indicate the mechanisms underlying ESCA progression at the layer of mRNA translation control and provide molecular insights for the development of effective cancer therapeutic strategies

RNA modification-related genes illuminate prognostic signature and mechanism in esophageal squamous cell carcinoma

Summary: Emerging studies have demonstrated the link between RNA modifications and various cancers, while the predictive value and functional mechanisms of RNA modification-related genes (RMGs) in esophageal squamous cell carcinoma (ESCC) remain unclear. Here we established a prognostic signature for ESCC based on five RMGs. The analysis of ESCC clinical samples further verified the prognostic power of the prognostic signature. Moreover, we found that the knockdown of NSUN6 promotes ESCC progression in vitro and in vivo, whereas the overexpression of NSUN6 inhibits the malignant phenotype of ESCC cells. Mechanically, NSUN6 mediated tRNA m5C modifications selectively enhance the translation efficiency of CDH1 mRNA in a codon dependent manner. Rescue assays revealed that E-cadherin is an essential downstream target that mediates NSUN6’s function in the regulation of ESCC progression. These findings offer additional insights into the link between ESCC and RMGs, as well as provide potential strategies for ESCC management and therapy