Background Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; however, its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11's expression and correlation with nuclear expression of nuclear factor erythroid-2 (NRF2)-associated radioresistance in ESCC. Methods We included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used to detect SLC7A11 and NRF2 nuclear expression, and the relationship between clinicopathological characteristics and survival rates or therapy response were evaluated. Western blot, dual-reporter assays and Chromatin immunoprecipitation (ChIP)-sequencing were used to analyze their relationship in vitro. Their roles in radioresistance were then investigated through multiple validation steps. Results NRF2 nuclear expression and SLC7A11 expression were overexpressed in ESCC tissues and were positively correlated with one another. NRF2 nuclear expression was significantly associated with tumor length, lymph node metastasis, and TNM stage, while SLC7A11 expression was associated with lymph node metastasis. Patients with high NRF2 nuclear expression and SLC7A11 expression had significantly shorter overall and progression-free survival, and poor treatment response. The multivariate model showed that NRF2 nuclear expression and SLC7A11 expression, sex and tumor location are independent prognostic factors. In vitro analysis confirmed that hyperactivation of NRF2 induced SLC7A11 expression by directly binding to its promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 expression, and radiotherapy-related ferroptosis morphologic features. Conclusion Our study reveals a connection between high SLC7A11 expression and NRF2 nuclear expression in patients with ESCC that was related to worse survival and poorer therapy outcomes. SLC7A11-mediated ferroptosis inhibition induced NRF2-associated radioresistance, highlighting potential of NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against therapy resistance biomarker.

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SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

A Critical Role of Nuclear m6A Reader YTHDC1 in Leukemogenesis by Regulating MCM Complex-Mediated DNA Replication

Ferroptosis is a type of oxidative stress-dependent regulated necrosis characterized by excessive lipid peroxide accumulation. This novel cell death modality has been implicated in preventing cancer progression. Cancer cells tend to modulate their redox state to prevent excessive peroxidation, eventually facilitating tumor growth. System Xc- (a cystine/glutamate antiporter system) is a promising target in cancer cells for ferroptosis induction. The overexpression of system Xc-, especially its core subunit xCT, has been reported in several tumors, and these high expression levels were closely related to cancer cell proliferation, invasion, metastasis and the tumor microenvironment. xCT might serve as a novel biomarker, and its upregulation almost always indicates drug tolerance and poor survival. Therefore, system Xc- inhibition may enhance chemotherapy sensitivity and optimize patient prognosis. Here, we elaborate on the mediation of ferroptosis by suppressing system Xc- and the relevant underlying molecular mechanism in cancer cells. The spotlight on this approach to cancer treatment is creating a new horizon and pointing to future opportunities.

System Xc - : a key regulatory target of ferroptosis in cancer.

Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. SIGNIFICANCE: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.

https://cancerres.aacrjournals.org/content/canres/81/13/3461.full.pdf

Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition

Enabling replicative immortality and uncontrolled cell cycle are hallmarks of cancer cells. Minichromosome maintenance proteins (MCMs) exhibit helicase activity in replication initiation and play vital roles in controlling replication times within a cell cycle. Overexpressed MCMs are detected in various cancerous tissues and cancer cell lines. Previous studies have proposed MCMs as promising proliferation markers in cancers, while the prognostic values remain controversial and the underlying mechanisms remain unascertained. This review provides an overview of the significant findings regarding the cellular and tumorigenic functions of the MCM family. Besides, current evidence of the prognostic roles of MCMs is retrospectively reviewed. This work also offers insight into the mechanisms of MCMs prompting carcinogenesis and adverse prognosis, providing information for future research. Finally, MCMs in liver cancer are specifically discussed, and future perspectives are provided.

https://downloads.hindawi.com/journals/acp/2020/3750294.pdf

MCMs in Cancer: Prognostic Potential and Mechanisms.

Solute carrier family 7, membrane 11 (SLC7A11) or (xCT) is a component of the cysteine-glutamate transporter, which plays a critical role in glutathione homeostasis which is important to protect cells from oxidative stress. SLC7A11 is distributed in various tissues and participates in the occurrence of a number of diseases, particularly in the pathogenesis of malignant tumors, but its role in laryngeal cancer development has not yet been clearly defined. The objective of the present study was to investigate the role of SLC7A11 in laryngeal squamous cell carcinoma (LSCC). We conducted immunohistochemistry and RT-PCR to evaluate the protein and mRNA levels of SLC7A11 in LSCC and in control tissues, respectively. The knockdown experiments were conducted with SLC7A11 short hairpin RNA (shRNA) lentivirus, and the protein and mRNA levels of SLC7A11 were assessed by RT-PCR and western blotting. The functional study of SLC7A11 in vitro was conducted by MTT assay, and the effects on the cell cycle were detected using flow cytometry. Immunohistochemical results revealed that the expression levels of SLC7A11, Ki-67 and p53 in LSCC tissues were higher than those in laryngeal dysplasia tissues. The Spearman rank correlation analysis revealed that the expression of SLC7A11 was positively correlated with the expression of p53 and Ki-67. Cox regression analysis and Kaplan-Meier plots confirmed that the expression levels of SLC7A11 were a prognostic factor for overall survival (OS) rates and postoperative recurrence of LSCC. Moreover, the functional study of SLC7A11 in vitro revealed that knockdown of SLC7A11 using shRNA inhibited cell proliferation by inducing cell cycle arrest at the G1 phase. Immunohistochemical and RT-PCR results and knockdown experiments of SLC7A11 revealed that SLC7A11 was involved in the progression of LSCC, and may provide clinical information for the evaluation of OS rates and postoperative recurrence of LSCC. Collectively, these observations suggest that SLC7A11 may be a vital biomarker for the diagnosis and prognosis in human LSCC, and targeting SLC7A11 appears to be a potentially significant method for LSCC treatment.

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SLC7A11, a component of cysteine/glutamate transporter, is a novel biomarker for the diagnosis and prognosis in laryngeal squamous cell carcinoma.

Purpose The minichromosomal maintenance (MCM) proteins are involved in the initiation and DNA replication. The role of MCM4 remains to be elucidated. The purpose of this study was to investigate the effects of MCM4 in laryngeal squamous cell carcinoma (LSCC) cell growth and apoptosis. Methods LSCC cell line UMSCC 5 was used in this study. The small interfering RNA (siRNA) of MCM 4 gene was used to identify the effects of MCM4 on the proliferation and apoptosis using methylimidazole tetrazolium (MTT) assay and flow-cytometry, respectively. Confirmed LSCC and adjacent non-tumor tissues were collected from 34 patients who were willing to participate in the study, from 2010 through 2015, from 163 patients undergoing treatment in the Department of Otorhinolaryngology/Head and Neck Surgery of Beijing Tongren Hospital in Capital Medical University of P.R. China. Immunohistochemical staining of MCM4 expression in the resected tissues was performed to analyze the correlation between its expression and the clinicopathological characteristics. Results The results showed that siRNA of MCM4 could significantly inhibit LSCC cell line UMSCC 5 proliferation and induce apoptosis. MCM4 mRNA was higher expressed in carcinoma tissues than in adjacent normal tissues. MCM4 expression was correlated with male gender, smoking history and poor differentiation. Conclusions We noticed a significant role for MCM4 overexpression in human LSCC tissues and their corresponding adjacent non-neoplastic tissues and found that siRNA of MCM4 can significantly decrease the proliferation of cancer cells. It is suggested that MCM4 profiling could potentially be used to predict response to treatment and prognosis in LSCC.

Minichromosome maintenance (MCM) protein 4 overexpression is a potential prognostic marker for laryngeal squamous cell carcinoma.

Mobile colistin resistance (mcr) genes represent an emerging threat to public health. Reports on the prevalence, antimicrobial profiles, and clonality of MCR-9-producing Enterobacter cloacae complex (ECC) isolates on a national scale in China are limited. We screened 3,373 samples from humans, animals, and the environment and identified eleven MCR-9-positive ECC isolates. We further investigated their susceptibility, epidemiology, plasmid profiles, genetic features, and virulence potential. Ten strains were isolated from severe bloodstream infection cases, especially three of them were recovered from neonatal sepsis. Enterobacter hormaechei was the most predominant species among the MCR-9-producing ECC population. Moreover, the co-existence of MCR-9, CTX-M, and SHV-12 encoding genes in MCR-9-positive isolates was globally observed. Notably, mcr-9 was mainly carried by IncHI2 plasmids, and we found a novel ~187 kb IncFII plasmid harboring mcr-9, with low similarity with known plasmids. In summary, our study presented genomic insights into genetic characteristics of MCR-9-producing ECC isolates retrieved from human, animal, and environment samples with one health perspective. This study is the first to reveal NDM-1- and MCR-9-co-producing ECC from neonatal sepsis in China. Our data highlights the risk for the hidden spread of the mcr-9 colistin resistance gene.

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Emergence of Neonatal Sepsis Caused by MCR-9- and NDM-1-Co-Producing Enterobacter hormaechei in China

Q fever is a zoonotic infectious disease caused by Coxiella burnetii. The clinical symptoms of acute Q fever are usually atypical, and routine serological tests of C. burnetii are not readily available, making the diagnosis of Q fever a challenge. In this case, we report a male patient who had repeated fevers and was administered empirical anti-infective treatment, but the effect was poor. After conducting relevant laboratory and imagological examinations, the etiology has not yet been confirmed. Subsequently, metagenomic next-generation sequencing (mNGS) identified the sequence reads of C. burnetii from the patient's peripheral blood within 48 h, and then the diagnosis of acute Q fever was established. Moreover, the serological test of indirect immunofluorescence assay (IFA) of the C. burnetii antibody was further performed in the Centers for Disease Control, certifying the result of mNGS. The patient was ultimately treated with doxycycline and recovered well. mNGS is an unbiased and comprehensive method in infrequent or culture-negative pathogen identification. To our knowledge, this is the first case of acute Q fever identified by mNGS and confirmed by IFA in Taizhou, China. A further large-scale prospective clinical cohort study is worth carrying out to compare the diagnostic efficiency of mNGS with traditional serological methods and PCR in acute Q fever.

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Jianfeng Han

Papers

SLC7A11, a component of cysteine/glutamate transporter, is a novel biomarker for the diagnosis and prognosis in laryngeal squamous cell carcinoma.

Minichromosome maintenance (MCM) protein 4 overexpression is a potential prognostic marker for laryngeal squamous cell carcinoma.

Emergence of Neonatal Sepsis Caused by MCR-9- and NDM-1-Co-Producing Enterobacter hormaechei in China

Case Report: Metagenomic Next-Generation Sequencing Clinches the Diagnosis of Acute Q Fever and Verified by Indirect Immunofluorescence Assay