Genome-wide identification of the SAUR gene family and screening for SmSAURs involved in root development in Salvia miltiorrhiza.

KEY MESSAGE: SmSAUR4, SmSAUR18, SmSAUR28, SmSAUR37, and SmSAUR38 were probably involved in the auxin-mediated root development in Salvia miltiorrhiza. Salvia miltiorrhiza is a widely utilized medicinal plant in China. Its roots and rhizomes are the main medicinal portions and are closely related to the quality of this herb. Previous studies have revealed that auxin plays pivotal roles in S. miltiorrhiza root development. Whether small auxin-up RNA genes (SAURs), which are crucial early auxin response genes, are involved in auxin-mediated root development in S. miltiorrhiza is worthy of investigation. In this study, 55 SmSAUR genes in S. miltiorrhiza were identified, and their physical and chemical properties, gene structure, cis-acting elements, and evolutionary relationships were analyzed. The expression levels of SmSAUR genes in different organs of S. miltiorrhiza were detected using RNA-seq combined with qRT‒PCR. The root development of S. miltiorrhiza seedlings was altered by the application of indole-3-acetic acid (IAA), and Pearson correlation coefficient analysis was conducted to screen SmSAURs that potentially participate in this physiological process. The diameter of primary lateral roots was positively correlated with SmSAUR4. The secondary lateral root number was positively correlated with SmSAUR18 and negatively correlated with SmSAUR4. The root length showed a positive correlation with SmSAUR28 and SmSAUR37 and a negative correlation with SmSAUR38. The fresh root biomass exhibited a positive correlation with SmSAUR38 and a negative correlation with SmSAUR28. The aforementioned SmSAURs were likely involved in auxin-mediated root development in S. miltiorrhiza. Our study provides a comprehensive overview of SmSAURs and provides the groundwork for elucidating the molecular mechanism underlying root morphogenesis in this species.

The RNA binding protein MEX3A promotes tumor progression of breast cancer by post-transcriptional regulation of IGFBP4.

PURPOSE: Breast cancer (BC) is the most frequent malignant tumor in women worldwide with exceptionally high morbidity. The RNA-binding protein MEX3A plays a crucial role in genesis and progression of multiple cancers. We attempted to explore its clinicopathological and functional significance in BC in which MEX3A is expressed. METHODS: The expression of MEX3A detected by RT-qPCR and correlated the results with clinicopathological variables in 53 BC patients. MEX3A and IGFBP4 profile data of BC patients were downloaded from TCGA and GEO database. Kaplan-Meier (KM) analysis was used to estimate the survival rate of BC patients. Western Blot, CCK-8, EdU, colony formation and flow cytometry were performed to investigate the role of MEX3A and IGFBP4 in BC cell proliferation, invasion and cell cycle in vitro. A subcutaneous tumor mouse model was constructed to analyze in vivo growth of BC cells after MEX3A knockdown. The interactions among MEX3A and IGFBP4 were measured by RNA pull-down and RNA immunoprecipitation. RESULTS: The expression of MEX3A was upregulated in BC tissues compared to adjacent tissues and high expression of MEX3A was associated with poor prognosis. Subsequent in vitro studies demonstrated that MEX3A knockdown inhibited BC cells proliferation and migration, as well as xenograft tumor growth in vivo. The expression of IGFBP4 was significantly negatively correlated with MEX3A in BC tissues. Mechanistic investigation showed that MEX3A binds to IGFBP4 mRNA in BC cells, decreasing IGFBP4 mRNA levels, which further activated the PI3K/AKT and other downstream signaling pathways implicated cell cycle progression and cell migration. CONCLUSION: Our results indicate that MEX3A plays a prominent oncogenic role in BC tumorigenesis and progression by targeting IGFBP4 mRNA and activating PI3K/AKT signaling, which can be used as a novel therapeutic target for BC.

Comparative transcriptome analysis reveals the regulatory effects of exogenous auxin on lateral root development and tanshinone accumulation in Salvia miltiorrhiza.

MAIN CONCLUSION: The physiological and transcriptome analysis revealed that auxin was a positive regulator of lateral root development and tanshinone accumulation in Salvia miltiorrhiza. Roots of S. miltiorrhiza are widely used as medicinal materials in China, and the root morphology and content of bioactive compounds [such as phenolic acids and diterpenoid quinones (tanshinones)] are the main factors to determine the quality of this herb. Auxin regulates root development and secondary metabolism in many plant species, but little is known about its function in S. miltiorrhiza. In this study, S. miltiorrhiza seedlings were treated (exogenous application) with the auxin indole-3-acetic acid (IAA) and the polar auxin transport inhibitor N-1-naphthylphthalamic acid (NPA) to investigate the regulatory roles of auxin in S. miltiorrhiza. The results indicated that exogenous IAA promoted both lateral root development and tanshinones biosynthesis in S. miltiorrhiza. The NPA application suppressed the lateral root development but showed no obvious effects on tanshinones accumulation. Based on the RNA-seq analysis, expressions of genes related to auxin biosynthesis and signaling transduction were altered in both treated groups. Coincidental with the enhanced content of tanshinones, transcripts of several key enzyme genes in the tanshinones biosynthetic pathway were stimulated after the exogenous IAA application. The expression profiles of seven common transcription factor domain-containing gene families were analyzed, and the results implied that some AP2/ERF genes were probably responsible for the auxin-induced lateral root development in S. miltiorrhiza. These findings shed new light on the regulatory roles of auxin on root development and bioactive compounds biosynthesis in S. miltiorrhiza, and lay the groundwork for future research into the detailed molecular mechanism underlying these biological functions.

A PET/CT nomogram incorporating SUVmax and CT radiomics for preoperative nodal staging in non-small cell lung cancer.

OBJECTIVES: To develop and validate a PET/CT nomogram for preoperative estimation of lymph node (LN) staging in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 263 pathologically confirmed LNs from 124 patients with NCSLC were retrospectively analyzed. Positron-emission tomography/computed tomography (PET/CT) examination was performed before treatment according to the clinical schedule. In the training cohort (N = 185), malignancy-related features, such as SUVmax, short-axis diameter (SAD), and CT radiomics features, were extracted from the regions of LN based on the PET/CT scan. The Minimum-Redundancy Maximum-Relevance (mRMR) algorithm and the Least Absolute Shrinkage and Selection Operator (LASSO) regression model were used for feature selection and radiomics score building. The radiomics score (Rad-Score) and SUVmax were incorporated in a PET/CT nomogram using the multivariable logistic regression analysis. The performance of the proposed model was evaluated with discrimination, calibration, and clinical application in an independent testing cohort (N = 78). RESULTS: The radiomics scores consisting of 14 selected features were significantly associated with LN status for both training cohort with AUC of 0.849 (95% confidence interval (CI), 0.796-0.903) and testing cohort with AUC of 0.828 (95% CI, 0.782-0.919). The PET/CT nomogram incorporating radiomics score and SUVmax showed moderate improvement of the efficiency with AUC of 0.881 (95% CI, 0.834-0.928) in the training cohort and AUC of 0.872 (95% CI, 0.797-0.946) in the testing cohort. The decision curve analysis indicated that the PET/CT nomogram was clinically useful. CONCLUSION: The PET/CT nomogram, which incorporates Rad-Score and SUVmax, can improve the diagnostic performance of LN metastasis. KEY POINTS: • The PET/CT nomogram (Int-Score) based on lymph node (LN) PET/CT images can reliably predict LN status in NSCLC. • Int-Score is a relatively objective diagnostic method, which can play an auxiliary role in the process of clinicians making treatment decisions.

Overexpression of serum lncRNA-ABHD11-AS1 as poor prognosis of patients with papillary thyroid carcinoma.

This paper was aimed at exploring the correlation of long non-coding RNA (lncRNA)-ABHD11 Antisense RNA1 (ABHD11-AS1) with the poor prognosis of patients with papillary thyroid carcinoma (PTC) and at investigating its effects on the survival of PTC cells. Serum was respectively collected from 64 PTC patients who were admitted to our hospital (PTC group) and from 50 healthy controls who underwent physical examinations (HC group) both from April 2011 to April 2015. The expression levels of ABHD11-AS1 in the serum were detected, and the values of it for diagnosis and prognosis (5-year follow-ups) were analyzed. The knockdown and overexpression models of ABHD11-AS1 in were constructed to explore the effects of the models on their proliferation, cycles and apoptosis. According to the data, the expression levels of serum ABHD11-AS1 in the PTC patients were remarkably higher than those in the healthy controls, and the area under the curve (AUC) for distinguishing the patients from the controls was 0.920. In the analysis of prognosis, the levels in patients with a poor prognosis were remarkably higher than those in patients with a good prognosis. According to the curves of overall survival rates (OSRs), the high levels of ABHD11-AS1 were remarkably correlated with the poor prognosis (a lower 5-year OSR). COX analysis showed that TNM staging, lymph node metastasis and ABHD11-AS1 were the independent prognostic factors of PTC patients. In the cell experiments, knocking down ABHD11-AS1 remarkably inhibited PTC cells from proliferation, arrested them in G0/G1 phase, and induced their apoptosis, negatively affecting their survival indices. Overexpressing this RNA had positive effects on the survival indices. Taken together, high levels of serum ABHD11-AS1 are related to the poor prognosis of PTC patients, and knocking down its expression can inhibit the survival of PTC cells.

Association analysis between the interaction of RAS family genes mutations and papillary thyroid carcinoma in the Han Chinese population.

Papillary thyroid carcinoma (PTC) is the major subtype of thyroid cancer, accounting for 75%-85% of all thyroid malignancies. This study aimed to identify the association between the interactions of single nucleotide polymorphisms (SNPs) in RAS family genes and PTC in the Han Chinese population, to provide clues to the pathogenesis and potential therapeutic targets for PTC. Hap Map and NCBI-db SNP databases were used to retrieve SNPs. Haploview 4.2 software was used to filter SNPs based on specific parameters, six SNPs of RAS gene (KRAS-rs12427141, KRAS-rs712, KRAS-rs7315339, HRAS-rs12628, NRAS-rs14804 and NRAS-rs2273267) were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) in 673 PTC patients and 657 healthy controls, the interactive effect was evaluated by crossover analysis, logistic regression and GMDR software. We found that genetic mutation in rs712 have significant associations with PTC risk after Bonferroni correction (p<0.001). The interaction between KRAS-rs12427141 and HRAS-rs12628 increased the risk of PTC (U=-2.119, p<0.05), the interaction between KRAS-rs2273267 and HRAS-rs7315339 reduced the risk of PTC (U=2.195, p<0.05). GMDR analysis showed that the two-factor model (KRAS-rs712, NRAS-rs2273267) was the best (p=0.0107). Summarily, there are PTC-related interactions between RAS family genes polymorphisms in the Han Chinese population.

Core Microbiome of Medicinal Plant Salvia miltiorrhiza Seed: A Rich Reservoir of Beneficial Microbes for Secondary Metabolism?

Seed microbiome includes special endophytic or epiphytic microbial taxa associated with seeds, which affects seed germination, plant growth, and health. Here, we analyzed the core microbiome of 21 Salvia miltiorrhiza seeds from seven different geographic origins using 16S rDNA and ITS amplicon sequencing, followed by bioinformatics analysis. The whole bacterial microbiome was classified into 17 microbial phyla and 39 classes. Gammaproteobacteria (67.6%), Alphaproteobacteria (15.6%), Betaproteobacteria (2.6%), Sphingobacteria (5.0%), Bacilli (4.6%), and Actinobacteria (2.9%) belonged to the core bacterial microbiome. Dothideomycetes comprised 94% of core fungal microbiome in S. miltiorrhiza seeds, and another two dominant classes were Leotiomycetes (3.0%) and Tremellomycetes (2.0%). We found that terpenoid backbone biosynthesis, degradation of limonene, pinene, and geraniol, and prenyltransferases, were overrepresented in the core bacterial microbiome using phylogenetic examination of communities by reconstruction of unobserved states (PICRUSt) software. We also found that the bacterial genera Pantoea, Pseudomonas, and Sphingomonas were enriched core taxa and overlapped among S. miltiorrhiza, maize, bean, and rice, while a fungal genus, Alternaria, was shared within S. miltiorrhiza, bean, and Brassicaceae families. These findings highlight that seed-associated microbiomeis an important component of plant microbiomes, which may be a gene reservoir for secondary metabolism in medicinal plants.

FasL -844T/C and Fas -1377G/A: mutations of pulmonary adenocarcinoma in South China and their clinical significances.

Apoptosis is an important mechanism of malignant tumor formation and progression. Single nucleotide polymorphisms (SNPs) located within cell death genes may influence cancer risk. We explored the relationship between FasL -844T/C and/or Fas -1377G/A SNPs and pulmonary adenocarcinoma (AD). Two hundred seventy-five patients with pulmonary AD of South China admitted into Zhejiang Cancer Hospital from July 2007 to October 2011 were randomly selected, and their clinicopathological data were collected at the same time. Two hundred ninety-seven cases of healthy individuals were selected as control. FasL -844T/C and Fas -1377G/A SNPs were detected by PCR-RFLP technique to evaluate the relationships between these two SNPs and pulmonary AD. Age, FasL -844 and Fas -1377 SNPs were associated with increased risk of pulmonary AD susceptibility in main effect analysis. FasL -844CC and Fas -1377 AA were associated with an increased risk for the development of pulmonary AD only in age <60 years people, but not in those ≥60 years. FasL -844CC genotype was associated with an increased risk for pulmonary AD (adjusted OR = 2.010, 95 % CI 1.196-3.379, P = 0.008) compared with TT genotype. However, Fas -1377 AA was a risk factor only when FasL -844 genotype was CC. Fas -1377 genotypes showed significant effect modification of pulmonary AD risk by FasL -844 genotype with test of the interaction term adjusting for age, gender, and FasL -844 SNP. Fas -1377G/A was not associated with the clinicopathological factors, while FasL -844C/T was associated with tumor stage and lymph node metastasis in age ≥60 years people and tumor stage in those <60 years. In conclusion, FasL -844 SNP is associated with the susceptibility of pulmonary AD in age <60 years people. Fas -1377 SNP may modify the association of FasL -844 SNP with the risk of pulmonary AD. FasL -844 genotype plays an important role in the occurrence and progression of pulmonary AD.

α-Adducin gene G614T polymorphisms in essential hypertension patients with high low density lipoprotein (LDL) levels.

BACKGROUND & OBJECTIVES: The association between α-adducin gene G614T polymorphism and essential hypertension (EH) is not clear. The present study was carried out to examine a possible association between α-adducin gene G614T mutation and essential hypertension in Chinese population. METHODS: A total of 170 patients with essential hypertension (EH group) and 154 normotensive subjects (Control group) were genotyped for the cytoskeletal protein single nucleotide polymorphism G614T of the α-adducin gene by PCR-RFLP technique. Systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), low density lipoprotein (LDL), high-density lipoprotein (HDL), high-sensitivity C-reactive protein (hs-CRP), left atrial diameter (LA DIA), left ventricular diameter (LV DIA) and other parameters were recorded in EH group. RESULTS: There was significant association between EH and α-adducin genotypes (P<0.05). GT and TT genotypes in EH group had higher LDL levels as compared to GG carriers (P<0.05). The LDL concentration was significantly elevated in patients with GT and TT genotypes. The LDL levels also differed significantly in male patients with all the three genotypes. INTERPRETATION & CONCLUSIONS: A significant association was found between ADD1 gene G614T polymorphism and EH in Chinese patients. Further studies need to be done to confirm these findings in a large sample.

[Research on expression of somatomedin b domain of proteoglycan 4 and recombinant protein aggregation].

Recombinant protein SMB(PRG4) containing two Somatomedin B domains and a small amount of glycosylation of repetitive sequences of proteoglycan 4 was cloned according to PGR4 gene polymorphism. Mature purification process was established and recombinant protein SMB(PRG4), with high-level expression was purified. By using size-exclusion chromatogaraphy and dynamic light scattering, we found that the recombinant protein self-aggregate to dimeric form. Structure prediction and non-reducing electrophoresis revealed that SMB(PRG4), was a non-covalently bonded dimer.

Lumbosacral Paravertebral Tophaceous Gout on an Adolescent Mimicking Malignant Neoplasm in 18 F-FDG PET/CT.

ABSTRACT: Contrast-enhanced MRI was performed on a 17-year-old adolescent boy with chronic lumbar and lower-limb pain, which had worsened over the past 3 days. It revealed a suspicious malignant mass adjacent to right appendage of L5-S1 vertebrae, with mixed signals and heterogeneous and obvious enhancement. 18 F-FDG PET/CT was subsequently performed for staging. It showed an FDG-avid mass with mixed density in right psoas major muscle, involving adjacent appendage of L5-S1 vertebrae. Histopathological examination confirmed the mass to be gouty tophus, characterized by nodular homogeneous pink amorphous deposits around the cartilage tissue, surrounded by histiocytes and multinucleated giant cells.

LncRNAs-circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers.

As one of novel hallmarks of cancer, lipid metabolic reprogramming has recently been becoming fascinating and widely studied. Lipid metabolic reprogramming in cancer is shown to support carcinogenesis, progression, distal metastasis, and chemotherapy resistance by generating ATP, biosynthesizing macromolecules, and maintaining appropriate redox status. Notably, increasing evidence confirms that lipid metabolic reprogramming is under the control of dysregulated non-coding RNAs in cancer, especially lncRNAs and circRNAs. This review highlights the present research findings on the aberrantly expressed lncRNAs and circRNAs involved in the lipid metabolic reprogramming of cancer. Emphasis is placed on their regulatory targets in lipid metabolic reprogramming and associated mechanisms, including the clinical relevance in cancer through lipid metabolism modulation. Such insights will be pivotal in identifying new theranostic targets and treatment strategies for cancer patients afflicted with lipid metabolic reprogramming.

miR-125b inhibits Connexin43 and promotes glioma growth.

MicroRNA is strongly associated with tumor growth and development. This study examined the potential roles of miR-125b in glioma growth. We found that miR-125b promotes glioma cell line growth and clone formation, and protects the glioma cells from apoptosis in vitro. The miR-125b-transfected glioma cells also demonstrated increased growth after in vivo transplantation. We further identified that miR-125b inhibits Connexin43 expression, and the overexpression of Connexin43 antagonizes the effects of miR-125b in cell growth and anti-apoptosis. We conclude that miR-125b regulates glioma growth partly through Connexin43 protein.

Effects of Zn deficiency, antioxidants, and low-dose radiation on diabetic oxidative damage and cell death in the testis.

Infertility is one of the common complications in diabetic men and mainly due to the loss of germ cells by apoptotic cell death. Although several mechanisms have been proposed to explain the induction of testicular cell death by diabetes, diabetic induction of testicular oxidative stress and damage may be the predominant mechanism responsible for the testicular cell death in diabetes. To explore whether factors that either increase or decrease the testicular oxidative stress and damage will enhance or prevent diabetes-induced testicular cell death, the effect of zinc (Zn) deficiency on diabetes-induced cell death has been examined since Zn was found to play an important role in the protection of testis from oxidative stress and damage. Zn deficiency, induced by its chelator N,N,N,N-Tetrakis(2-pyridylmethyl)-1,2-ethylenediamine, was found to exacerbate diabetes-induced testicular oxidative damage and cell death. In contrast, treatment of diabetic rats with antioxidant N-acetylcysteine or low-dose radiation that can up-regulate endogenous antioxidants significantly attenuated diabetes-induced testicular cell death. These results suggest that diabetes-induced testicular cell death that may eventually cause men's infertility is predominantly mediated by the oxidative stress and damage. To prevent or delay diabetes-caused infertility, diabetic patients should avoid Zn deficiency, and might consider antioxidant supplementation.

Gut microbiota: A novel and potential target for radioimmunotherapy in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate, and is a major burden on human health worldwide. Gut microbiota regulate human immunity and metabolism through producing numerous metabolites, which act as signaling molecules and substrates for metabolic reactions in various biological processes. The importance of host-gut microbiota interactions in immunometabolic mechanisms in CRC is increasingly recognized, and interest in modulating the microbiota to improve patient's response to therapy has been raising. However, the specific mechanisms by which gut microbiota interact with immunotherapy and radiotherapy remain incongruent. Here we review recent advances and discuss the feasibility of gut microbiota as a regulatory target to enhance the immunogenicity of CRC, improve the radiosensitivity of colorectal tumor cells and ameliorate complications such as radiotoxicity. Currently, great breakthroughs in the treatment of non-small cell lung cancer and others have been achieved by radioimmunotherapy, but radioimmunotherapy alone has not been effective in CRC patients. By summarizing the recent preclinical and clinical evidence and considering regulatory roles played by microflora in the gut, such as anti-tumor immunity, we discuss the potential of targeting gut microbiota to enhance the efficacy of radioimmunotherapy in CRC and expect this review can provide references and fresh ideas for the clinical application of this novel strategy.

Multiple-Organ Involvement of Malakoplakia Mimicking Malignant Neoplasms on 18 F-FDG PET/CT.

ABSTRACT: Abdominal contrast-enhanced CT was performed in a 61-year-old man with difficulties of urination and defecation for 4 months, which revealed huge rectal masses involving multiple adjacent organs, suspected as malignant lesions. 18 F-FDG PET/CT was subsequently performed for staging. The images showed intense FDG uptake and slightly hyperdense masses involving rectum, bladder, prostate, left ureter, and the anterior abdominal wall at the level of the pelvic cavity. Histopathological examination confirmed the masses were due to malakoplakia, which displayed as abundant von Hansemann cells aggregated and infiltrated in lesions, with distinctive cytoplasmic inclusions termed Michaelis-Gutmann bodies.

WITHDRAWN: Stromal Cell-Derived Factor 1 Secreted by Cancer- Associated Fibroblasts Promotes lncRNA Xist through CXCR4 and Facilitates Invasion and Metastasis of Non-Small Cell Lung Cancer

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Systematic Identification and Validation of Suitable Reference Genes for the Normalization of Gene Expression in Prunella vulgaris under Different Organs and Spike Development Stages.

The quantitative real-time PCR (qRT-PCR) is an efficient and sensitive method for determining gene expression levels, but the accuracy of the results substantially depends on the stability of the reference gene (RG). Therefore, choosing an appropriate reference gene is a critical step in normalizing qRT-PCR data. Prunella vulgaris L. is a traditional Chinese medicine herb widely used in China. Its main medicinal part is the fruiting spike which is termed Spica Prunellae. However, thus far, few studies have been conducted on the mechanism of Spica Prunellae development. Meanwhile, no reliable RGs have been reported in P. vulgaris. The expression levels of 14 candidate RGs were analyzed in this study in various organs and at different stages of Spica Prunellae development. Four statistical algorithms (Delta Ct, BestKeeper, NormFinder, and geNorm) were utilized to identify the RGs' stability, and an integrated stability rating was generated via the RefFinder website online. The final ranking results revealed that eIF-2 was the most stable RG, whereas VAB2 was the least suitable as an RG. Furthermore, eIF-2 + Histon3.3 was identified as the best RG combination in different periods and the total samples. Finally, the expressions of the PvTAT and Pv4CL2 genes related to the regulation of rosmarinic acid synthesis in different organs were used to verify the stable and unstable RGs. The stable RGs in P. vulgaris were originally identified and verified in this work. This achievement provides strong support for obtaining a reliable qPCR analysis and lays the foundation for in-depth research on the developmental mechanism of Spica Prunellae.

CKAP2L Promotes Esophageal Squamous Cell Carcinoma Progression and Drug-Resistance by Modulating Cell Cycle.

Esophageal squamous cell carcinoma (ESCC) is one of the most common types of cancer and the leading cause of cancer-related mortality worldwide, especially in Asia. In this study, the gene CKAP2L was selected by GEO, TCGA, and GTEx database analysis. The high expression of CKAP2L is related to the occurrence and development of ESCC. In addition, CKAP2L knockdown can inhibit the growth and migration of ESCC cells, while CKAP2L overexpression has the opposite effect. Furthermore, in vivo experiments indicated that down-regulation of CKAP2L can inhibit the tumorigenesis of ESCC cells. KEGG pathway analysis and the STRING database explored the relationship between cell cycle and CKAP2L and verified that depletion of CKAP2L markedly arrested cell cycle in the G2/M phase. Meanwhile, CKAP2L knockdown increased the sensitivity of ESCC cells to flavopiridol, the first CDK inhibitor to be tested in clinical trials, leading to an observable reduction in cell proliferation and an increase in cellular apoptosis. In brief, we identified CKAP2L as a tumor promoter, potential prognostic indicator, and therapeutic target of ESCC, which may play a role in regulating cell cycle progression.

Hypoxia-responsive circRNAs: A novel but important participant in non-coding RNAs ushered toward tumor hypoxia.

Given the rapid developments in RNA-seq technologies and bioinformatic analyses, circular RNAs (circRNAs) have gradually become recognized as a novel class of endogenous RNAs, characterized by covalent loop structures lacking free terminals, which perform multiple biological functions in cancer genesis, progression and metastasis. Hypoxia, a common feature of the tumor microenvironments, profoundly affects several fundamental adaptive responses of tumor cells by regulating the coding and non-coding transcriptomes and renders cancer's phenotypes more aggressive. Recently, hypoxia-responsive circRNAs have been recognized as a novel player in hypoxia-induced non-coding RNA transcriptomics to modulate the hypoxic responses and promote the progression and metastasis of hypoxic tumors. Moreover, via extracellular vesicles-exosomes, these hypoxia-responsive circRNAs could transmit hypoxia responses from cancer cells to the cells of surrounding matrices, even more distant cells of other organs. Here, we have summarized what is known about hypoxia-responsive circRNAs, with a focus on their interaction with hypoxia-inducible factors (HIFs), regulation of hypoxic responses and relevance with malignant carcinoma's clinical features, which will offer novel insights on the non-coding RNAs' regulation of cancer cells under hypoxic stress and might aid the identification of new theranostic targets and define new therapeutic strategies for those cancer patients with resistance to radiochemotherapy, because of the ubiquity of tumoral hypoxia.