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Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and are related to tumor proliferation, metastasis, relapse, and drug resistance. With the development of sequencing technologies, single-cell RNA sequencing has become a popular method for identifying CAFs in the tumor microenvironment. Whereas the drawbacks of CAFs, such as the lack of a spatial landscape, still exist, recent research has utilized spatial transcriptomics combined with single-cell RNA sequencing to address this issue. These multiomics analyses can resolve the single-cell resolution problem in spatial transcriptomics. In this review, we summarized the recent literature regarding the targeting of CAFs to address drug resistance, angiogenesis, metabolic reprogramming and metastasis in tumor tissue. [ABSTRACT FROM AUTHOR]

Background: Cancer is a thorny problem which cannot be conquered by mankind at present and recent researchers have put their focus on tumor microenviroment. Neutrophils, the prominent leukocytes in peripheral blood that accumulate in tumours, serves as frontline cells in response to tumour progression owing to the rapid development of micro biotechnology. Hence, targeted therapy with these neutrophils has made targeting treatment a promising field in cancer therapy. Main body: We broadly summarise some studies on the phenotypes and functions of tumour‐associated neutrophils as well as the unique web‐like products of neutrophils that play a role in cancer progression—neutrophil extracellular traps—and the interactions between neutrophils and the tumour microenvironment. Moreover, several targeted neutrophils therapeutic studies have made some progress and provided potential strategies for the treatment of cancer. Conclusion: This review aims to offer a holistic perspective on therapeutic interventions targeting neutrophils to further inspire more researches on cancer therapies. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis plays vital roles in the growth and metastasis of cancer. RNA methylation is one of the most common modifications and is widely observed in eukaryotes and prokaryotes. Accumulating studies have revealed that RNA methylation affects the occurrence and development of various tumors. In recent years, RNA methylation has been shown to play an important role in regulating tumor angiogenesis. In this review, we mainly elucidate the mechanisms and functions of RNA methylation on angiogenesis and progression in several cancers. We then shed light on the role of RNA methylation-associated factors and pathways in tumor angiogenesis. Finally, we describe the role of RNA methylation as potential biomarker and novel therapeutic target. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m6A profiling in 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 m6A peaks with 195 hyper-methylated and 93 hypo-methylated in PDAC compared with adjacent normal tissues. The differential m6A modifications distinguish two PDAC subtypes with different prognosis outcomes. The formation of the two subtypes is driven by a newly identified m6A regulator CSTF2 that co-transcriptionally regulates m6A installation through slowing the RNA Pol II elongation rate during gene transcription. We find that most of the CSTF2-regulated m6As have positive effects on the RNA level of host genes, and CSTF2-regulated m6As are mainly recognized by IGF2BP2, an m6A reader that stabilizes mRNAs. These results provide a promising PDAC subtyping strategy and potential therapeutic targets for precision medicine of PDAC. N6-methyladenosine (m6A) modification has important implications in different cancer subtypes. Here, the authors perform transcriptomic m6A profiling to identify two subtypes of pancreatic ductal adenocarcinoma with differential m6A modifications and different clinical outcomes, which is driven by m6A regulator CSTF2. [ABSTRACT FROM AUTHOR]

As a new infectious disease, COVID-19 is spread through the respiratory tract in most cases. Its source and pathological mechanism are not clear. The most common clinical feature is pulmonary infection. Also, a lot patients have gastrointestinal symptoms. Angiotensin-converting enzyme 2 (ACE2) is a functional cellular receptor for SARS-CoV-2, which is like SARS-CoV, a coronavirus associated with severe acute respiratory syndrome (SARS) outbreak in 2003. The tissues and cells expressing ACE2 are potential targets for SARS-CoV-2 infection, and the high expression of ACE2 in intestinal epithelial cells marks that SARS-CoV-2 may directly infect intestinal epithelial cells. Recent studies also suggest that SARS-CoV-2 existed and replicated in intestinal environment for a long time. The interaction between SARS-CoV-2 and RAS system leads to the decrease of local anti-inflammatory ability. The virus cycle leads to excessive imbalance of immune response and cytokine release. The downregulation of ACE2 after viral infection leads to gastrointestinal dysfunction. The above are the causes of gastrointestinal symptoms. Here, we reviewed the possible causes and mechanisms of gastrointestinal symptoms caused by COVID-19. Additionally, we discussed the influence of gastrointestinal symptoms on the prognosis of patients. [ABSTRACT FROM AUTHOR]

In recent years, an increasing number of studies have reported that intestinal microbiota have an important effect on tumour immunity by affecting the tumour microenvironment (TME). The intestinal microbiota are closely associated with various immune cells, such as T lymphocytes, natural killer cells (NK cells) and macrophages. Some bacteria, such as Akkermansia muciniphila (A. muciniphila) and Lactobacillus reuteri (L. reuteri), have been shown to improve the effect of tumour immunity. Furthermore, microbial imbalance, such as the increased abundance of Fusobacterium nucleatum (F. nucleatum) and Helicobacter hepaticus (H. hepaticus), generally causes tumour formation and progression. In addition, some microbiota also play important roles in tumour immunotherapy, especially PD‐L1‐related therapies. Therefore, what is the relationship between these processes and how do they affect each other? In this review, we summarize the interactions and corresponding mechanisms among the intestinal microbiota, immune system and TME to facilitate the research and development of new targeted drugs and provide new approaches to tumour therapy. [ABSTRACT FROM AUTHOR]

Cancer metastasis is a symptom of adverse prognosis, a prime origin of therapy failure, and a lethal challenge for cancer patients. N 6-methyladenosine (m6A), the most prevailing modification in messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) of higher eukaryotes, has attracted increasing attention. Growing studies have verified the pivotal roles of m6A methylation in controlling mRNAs and ncRNAs in diverse physiological processes. Remarkably, recent findings have showed that aberrant methylation of m6A-related RNAs could influence cancer metastasis. In this review, we illuminate how m6A modifiers act on mRNAs and ncRNAs and modulate metastasis in several cancers, and put forward the clinical application prospects of m6A methylation. [ABSTRACT FROM AUTHOR]

Background: Previous studies on the systemic immune-inflammation index (SII), which is based on platelet, neutrophil and lymphocyte counts, as a prognostic marker in patients with colorectal cancer (CRC) yielded inconsistent results. The aim of this study was to evaluate the prognostic and clinicopathological role of SII in CRC via meta-analysis. Methods: A comprehensive literature survey was performed on PubMed, Web of Science, Embase and the Cochrane Library databases to include studies published up to 6 April 2020. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed to estimate the prognostic and clinicopathological value of SII in CRC. Results: A total of 12 studies published between 2016 and 2019 were included in our meta-analysis. The combined analysis showed that high SII levels were significantly associated with worse overall survival (OS; HR = 1.61, 95% CI = 1.21–2.13, p = 0.001) and progression-free survival (HR = 1.74, 95% CI = 1.26–2.39, p = 0.001) in CRC. Moreover, elevated SII was also correlated with poor tumor differentiation (OR = 1.60, 95% CI = 1.27–2.02, p < 0.001), presence of distant metastasis (OR = 2.27, 95% CI = 1.10–4.67, p = 0.026), ECOG PS of 1–2 (OR = 1.98, 95% CI = 1.39–2.84, p < 0.001) and tumor size ⩾5 cm (OR = 1.49, 95% CI = 1.18–1.88, p = 0.001). However, high SII was not significantly associated with sex, tumor location, lymph node metastasis, or age in patients with CRC. Conclusion: Our meta-analysis indicated that high SII levels predicted poor prognosis in CRC. In addition, an elevated SII was also associated with clinical factors, implying higher malignancy of the disease. [ABSTRACT FROM AUTHOR]

The tumour microenvironment (TME) constitutes the area surrounding the tumour during its development and has been demonstrated to play roles in cancer-related diseases through crosstalk with tumour cells. Circular RNAs (circRNAs) are a subpopulation of endogenous noncoding RNAs (ncRNAs) that are ubiquitously expressed in eukaryotes and have multiple biological functions in the regulation of cancer onset and progression. An increasing number of studies have shown that circRNAs participate in the multifaceted biological regulation of the TME. However, details on the mechanisms involved have remained elusive until now. In this review, we analyse the effects of circRNAs on the TME from various perspectives, including immune surveillance, angiogenesis, hypoxia, matrix remodelling, exo-circRNAs and chemoradiation resistance. Currently, the enormous potential for circRNA use in targeted therapy and as noninvasive biomarkers have drawn our attention. We emphasize the prospect of targeting circRNAs as an essential strategy to regulate TME, overcome cancer resistance and improve therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Aimei Rong,2 Quanbo Zhou,3 Wenlu Li41Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; 2Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450000, China; 3Department of Anus and Intestine Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; 4Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China Background: Claudin 8 (CLDN8), an integral membrane protein that constitutes tight junctions in cell membranes, was recently implicated in tumor progression. However, its roles in colorectal cancer (CRC) progression and metastasis remain unknown. Methods: In this study, we examined the effect of CLDN8 on the progression of CRC, including cell proliferation, migration, and invasion, and determines its underlying molecular mechanism using in vitro CRC cell lines and in vivo mouse xenograft models. Results: We found that CLDN8 expression in human CRC tissues was significantly higher than that in adjacent normal tissues. The knockdown of CLDN8 markedly suppressed the proliferation, migration, and invasion of SW480 and HT-29 CRC cells, whereas the overexpression of CLDN8 notably promoted tumor progression in SW480 and HT-29 CRC cells. Mechanistic studies revealed that CLDN8 upregulated p-ERK (p-PKB/AKT) and MMP9 in CRC cells. Notably, the MAPK/ERK inhibitor PD98095 dramatically attenuated the effects of CLDN8 on p-ERK and MMP9. Moreover, PD98095 remarkably blocked the tumor-promoting activity of CLDN8. The knockdown of CLDN8 also inhibited the in vivo tumor growth in a nude mouse xenograft model. Collectively, CLDN8 promoted CRC cell proliferation, migration, and invasion, at least in part, by activating the MAPK/ERK signaling pathway. Conclusion: These findings suggest that CLDN8 exhibits an oncogenic effect in human CRC progression. [ABSTRACT FROM AUTHOR]

Background: Colon adenocarcinoma (COAD) is ranked as the third most commonly diagnosed cancer in both women and men, and it is the most frequently occurring malignant tumor. Dynactin is a protein compound based on multiple subunits, including dynactin 1–6 (DCTN1–6), in most categories of cytoplasmic dynein performance in eukaryotes. Nevertheless, correlations between the DCTN family and the prognosis and diagnosis of COAD remain unidentified.Methods: Statistics for DCTN mRNA expression in patients with COAD were acquired from The Cancer Genome Atlas. Kaplan–Meier analyses and a Cox regression model were applied to determine overall survival, with computation of HRs and 95% CIs. Several online data portals were used to assess the biological process, and pathway examination was performed using the Kyoto Encyclopedia of Genes and Genomes to predict the biological functionality of DCTN genes.Results: We found that high expression of DCTN4 was linked with satisfactory results for overall survival (P=0.042, HR=0.650, 95% CI 0.429–0.985). The expression of DCTN1, DATN2, and DCTN4 was closely correlated with the frequency of colon tumors (P<0.001, area under the curve [AUC]=0.8811, 95% CI 0.8311–0.9312; P<0.001, AUC=0.870, 96% CI 0.833–0.9071; and P=0.0051, AUC=0.6317, 95% CI 0.5725–0.6908, respectively). In the enrichment examination, the level of gene expression was related to the cell cycle, cell apoptosis, and the cell metastasis pathway.Conclusion: The expression levels of DCTN1, DCTN2, and DCTN4 could allow differentiation between cancer-bearing tissues and paracancerous tissue. These genes can be applied as biomarkers to predict the prognosis and diagnosis of COAD. [ABSTRACT FROM AUTHOR]

The present study aimed to determine how the expression and function of HOTTIP modifies, and regulates the metabotropic glutamate receptor 1 (mGluR1) to affect human pancreatic cancer cell viability. HOTTIP expression was higher in human pancreatic cancer tissue compared with in para-carcinoma tissue. However, downregulation of HOTTIP expression was revealed to significantly reduce cell viability, induce apoptosis, promote caspase-3 and caspase-8 activities and increase Bax expression in pancreatic cancer cells. Additionally, downregulation of HOTTIP expression significantly suppressed mGluR1 and mitigated activation of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway in pancreatic cancer cells. To the best of our knowledge, the present study is the first to identify that the anticancer effect of HOTTIP against human pancreatic cancer functions the mGluR1 pathway. [ABSTRACT FROM AUTHOR]

Noncoding RNAs (ncRNAs) can be divided into microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), pRNAs, and tRNAs. Traditionally, miRNAs exert their biological function mainly through the inhibition of translation via the induction of target RNA transcript degradation. lncRNAs and circRNAs were once considered to have no potential to code proteins. Here, we will review the current knowledge on ncRNAs in relation to their origins, characteristics, and functions. We will also review how ncRNAs work as competitive endogenous RNA, gene transcription and expression regulators, and RNA-binding protein sponges in colorectal cancer (CRC). Notably, except for the abovementioned mechanisms, recent advances revealed that lncRNAs can also act as the precursor of miRNAs, and a small portion of lncRNAs and circRNAs was verified to have the potential to code proteins, providing new evidence for the significance of ncRNAs in CRC tumorigenesis and development. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignancies in the world. Easier recurrence and metastasis is the main cause of mortality in CRC patients, and the markers applied for diagnosis and treatment of CRC is still urgently needed to early diagnose and evaluate therapeutic effect. Long noncoding RNA (lncRNA) is a class of noncoding RNA that the length is more than 200 nucleotides. With the development of sequencing technique about transcriptome, increasing lncRNAs are focused on their function and mechanism related to the nosogenesis and pathology of CRC. Recent studies report that lncRNAs acted as crucial role in CRC and could be as biomarker for CRC diagnosis and treatment. In this review, we display the regulation of lncRNA by interacting with DNA, RNA and protein and highlight the double role of lncRNAs as oncogene or anti-tumor gene involved in Wnt signaling pathway, p53 signaling pathway or others to be an regulator in CRC development. Lastly, we discuss some new finding of lncRNAs, especially lncRNA in exosome, which could be as potential markers for diagnosis and treatment of CRC in future. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic neuroendocrine tumors (PNETs) exhibit various tumor behaviors and symptoms that are difficult for physicians to stage and predict prognosis. We assess prognostic factors combined with staging classifications to optimal the models and try to improve follow-up strategy to monitor liver metastases after surgery.Methods: Patients with PNETs treated at Sun Yat-sen Memorial Hospital between 2000 and 2015 were recruited. Patients were regrouped on the basis of functional status and mitotic rates. Nomograms to predict the prognostic values of classifications (AJCC, ENETS, and WHO) were constructed; the accuracy of the nomograms were quantified by the C-index and calibration plots.Results: We identified 78 PNETs patients with pathological reports. Correlations with OS in univariate analysis included nonfunctional status (P = 0.002), CgA>200 ng/ml (P < 0.001), Ki-67 (3-20%, P = 0.014; >20%, P < 0.001), and mitotic rate (3-20/10HPF, P = 0.011; >20/10HPF, P < 0.001). By multivariate analysis, nonfunctional status and mitotic rate maintained significance (P = 0.039; 3-20/10HPF, P = 0.015; >20/10HPF, P = 0.007). Evaluating the new proposed system, the difference in OS between low- and high-groups was statistically significant (P = 0.001). The C-index of the regrouped nomograms were higher than that of premise ones (AJCC cohort, 0.605 v 0.576, P < 0.01; ENETS cohort, 0.73 v 0.691, P < 0.01; WHO cohort, 0.678 v 0.603, P < 0.01).Conclusion: An prognostic model based on mitotic rates and functional status correlates strongly with survival. PNETs should return visits every 2 months for the first half years, and every 3 months as followed until 2 years after surgery. [ABSTRACT FROM AUTHOR]

Introduction: The aim of present study was to profile the glucose-dependent and glutamine- dependent metabolism in pancreatic cancer. Methods: We performed Immunohistochemical staining of GLUT1, CAIX, BNIP3, p62, LC3, GLUD1, and GOT1. Based on the expression of metabolism-related proteins, the metabolic phenotypes of tumors were classified into two categories, including glucose- and glutamine-dependent metabolism. There were Warburg type, reverse Warburg type, mixed type, and null type in glucose-dependent metabolism, and canonical type, non-canonical type, mixed type, null type in glutamine-dependent metabolism. Results: Longer overall survival was associated with high expression of BNIP3 in tumor (p = 0.010). Shorter overall survival was associated with high expression of GLUT1 in tumor (P = 0.002) and GOT1 in tumor (p = 0.030). Warburg type of glucose-dependent metabolism had a highest percentage of tumors with nerve infiltration (P = 0.0003), UICC stage (P = 0.0004), and activated autophagic status in tumor (P = 0.0167). Mixed type of glucose-dependent metabolism comprised the highest percentage of tumors with positive marginal status (P<0.0001), lymphatic invasion (P<0.0001), and activated autophagic status in stroma (P = 0.0002). Mixed type and Warburg type had a significant association with shorter overall survival (P = 0.018). Non-canonical type and mixed type of glutamine-dependent metabolism comprised the highest percentage of tumors with vascular invasion (p = 0.0073), highest percentage of activated autophagy in tumors (P = 0.0034). Moreover, these two types of glutamine-dependent metabolism were significantly associated with shorter overall survival (P<0.001). Further analysis suggested that most of tumors were dependent on both glucose- and glutamine-dependent metabolism. After dividing the tumors according to the number of metabolism, we found that the increasing numbers of metabolism subtypes inversely associated with survival outcome. Conclusion: Warburg type, non-canonical type and mixed types of glucose- and glutamine-dependent metabolism comprised of more metabolically active, biologically aggressive and poor prognostic tumors. Moreover, the increasing subtypes and categories of the metabolism in each tumor significantly associated with poor prognosis. [ABSTRACT FROM AUTHOR]

T-helper (Th) 2 polarization functions in a number of immune diseases, but their pathogenesis needs further investigation. Some microbial products or components are strong adjuvants in the creation of mouse models of Th2 polarization. T cell immunoglobulin mucin molecule (TIM) 4 is a facilitator in the initiation of Th2 response. This study looks at the role of one of the microbial products, flagellin (FGN), in the induction of TIM4 expression in mast cells. Bone marrow derived mast cells (BMMC) were generated. Induction of TIM4 in mast cells was assessed in both experiments in vitro and in vivo. The signal transducer and activator of transcription 6 (Stat6) phosphorylation in BMMC were assessed by Western blotting. A coculture model with FGN-primed BMMC and naïve CD4+ T cells was employed to assess FGN in facilitating the expression of TIM4 in mast cells. After exposure to FGN, TIM4 levels were significantly increased in BMMC and mast cells of the mouse intestine, which was accompanied by increased STAT6 phosphorylation. Culture with FGN-primed BMMC, naïve CD4+ T cells developed into Th2 cells by a TIM4-dependent manner. We conclude that FGN can induce mast cells to express TIM4, which helps initiate Th2 polarization. [ABSTRACT FROM AUTHOR]

Abstract: Hepatitis C Virus core protein (HCVc) plays important roles in the development of intrahepatic cholangiocarcinoma (ICC). MicroRNAs (miRNAs) contribute to tumor progression by interacting with downstream target genes. However, the regulation and role of miRNAs in HCV-related intrahepatic cholangiocarcinoma (HCV-ICC) is poorly understood. In this study, we found that miR-124 was down-regulated in HCV-ICC and the induction of DNMT1 by HCVc mediated the suppression of miR-124. Over-expression of miR-124 suppressed cell migration and invasion in vitro, and reduced the protein levels of SMYD3 and downstream target genes (c-Myc and MMP9). Knockdown of SMYD3 inhibited cell migration and invasion resembling that of miR-124 over-expression. In conclusion, our studies indicate that low miR-124 levels mediated by HCVc via DNMT1 promote ICC cell migration and invasion by targeting SMYD3. [Copyright &y& Elsevier]

N6-methyladenosine (m6A) methylation, one of the most common RNA modifications, has been reported to execute important functions that affect normal life activities and diseases. Most studies have suggested that m6A modification can affect the complexity of cancer progression by regulating biological functions related to cancer. M6A modification of noncoding RNAs regulates the cleavage, transport, stability, and degradation of noncoding RNAs themselves. It also regulates cell proliferation and metastasis, stem cell differentiation, and homeostasis in cancer by affecting the biological function of cells. Interestingly, noncoding RNAs also play significant roles in regulating these m6A modifications. Additionally, it is becoming increasingly clear that m6A and noncoding RNAs potentially contribute to the clinical application of cancer treatment. In this review, we summarize the effect of the interactions between m6A modifications and noncoding RNAs on the biological functions involved in cancer progression. In particular, we discuss the role of m6A and noncoding RNAs as possible potential biomarkers and therapeutic targets in the treatment of cancers. [ABSTRACT FROM AUTHOR]

Exosomes have emerged as critical mediators of intercellular communication, both locally and systemically, by regulating a diverse range of biological processes between cells. Circular RNA (circRNA) is a novel member of endogenous noncoding RNAs with widespread distribution and diverse cellular functions. Recently, circular RNAs have been identified for their enrichment and stability in exosomes. In this review, we outline the origin, biogenesis and function of exosomal circRNAs as well as their roles in various diseases. Although their precise roles and mechanisms of gene regulation remain largely elusive, exosomal circRNAs have potential applications as disease biomarkers and novel therapeutic targets. [ABSTRACT FROM AUTHOR]