Regulation Of Tumor Progression Research Articles

Syntaphilin Regulates Neutrophil Migration in Cancer.

Pathologically activated neutrophils (PMN) with immunosuppressive activity, which are termed myeloid-derived suppressor cells (PMN-MDSC), play a critical role in regulating tumor progression. These cells have been implicated in promoting tumor metastases by contributing to premetastatic niche formation. This effect was facilitated by enhanced spontaneous migration of PMN from bone marrow to the premetastatic niches during the early-stage of cancer development. The molecular mechanisms underpinning this phenomenon remained unclear. In this study, we found that syntaphilin (SNPH), a cytoskeletal protein previously known for anchoring mitochondria to the microtubule in neurons and tumor cells, could regulate migration of PMN. Expression of SNPH was decreased in PMN from tumor-bearing mice and patients with cancer as compared with PMN from tumor-free mice and healthy donors, respectively. In Snph-knockout (SNPH-KO) mice, spontaneous migration of PMN was increased and the mice showed increased metastasis. Mechanistically, in SNPH-KO mice, the speed and distance travelled by mitochondria in PMN was increased, rates of oxidative phosphorylation and glycolysis were elevated, and generation of adenosine was increased. Thus, our study reveals a molecular mechanism regulating increased migratory activity of PMN during cancer progression and suggests a novel therapeutic targeting opportunity.

The role of extracellular vesicles and interleukin-8 in regulating and mediating neutrophil-dependent cancer drug resistance.

Tumor drug resistance is a multifactorial and heterogenous condition that poses a serious burden in clinical oncology. Given the increasing incidence of resistant tumors, further understanding of the mechanisms that make tumor cells able to escape anticancer drug effects is pivotal for developing new effective treatments. Neutrophils constitute a considerable proportion of tumor infiltrated immune cells, and studies have linked elevated neutrophil counts with poor prognosis. Tumor-associated neutrophils (TANs) can acquire in fact immunoregulatory capabilities, thus regulating tumor progression and resistance, or response to therapy. In this review, we will describe TANs' actions in the tumor microenvironment, with emphasis on the analysis of the role of interleukin-8 (IL-8) and extracellular vesicles (EVs) as crucial modulators and mediators of TANs biology and function in tumors. We will then discuss the main mechanisms through which TANs can induce drug resistance, finally reporting emerging therapeutic approaches that target these mechanisms and can thus be potentially used to reduce or overcome neutrophil-mediated tumor drug resistance.

Role of STAT3 and NRF2 in Tumors: Potential Targets for Antitumor Therapy.

Signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid-derived 2-like 2 (NRF2, also known as NFE2L2), are two of the most complicated transcription regulators, which participate in a variety of physiological processes. Numerous studies have shown that they are overactivated in multiple types of tumors. Interestingly, STAT3 and NRF2 can also interact with each other to regulate tumor progression. Hence, these two important transcription factors are considered key targets for developing a new class of antitumor drugs. This review summarizes the pivotal roles of the two transcription regulators and their interactions in the tumor microenvironment to identify potential antitumor drug targets and, ultimately, improve patients' health and survival.

Let-7b-5p inhibits colon cancer progression by prohibiting APC ubiquitination degradation and the Wnt pathway by targeting NKD1.

Naked cuticle homolog 1 (NKD1), which is expressed at low levels in many tumors, is considered an inhibitor of the Wnt/β-catenin pathway, but it is highly expressed in colon cancer and can promote colon cancer cell proliferation. miRNAs are involved in the occurrence and progression of many tumors. However, miRNAs that can regulate NKD1 and the mechanisms by which NKD1 regulates tumor progression remain ambiguous. This research aims to reveal the potential regulatory network of NKD1 in colon cancer. miRNA data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed by bioinformatics to screen for potential miRNAs targeting NKD1. Let-7b-5p was found to inhibit proliferation, migration, and invasion of colon cancer cells targeting NKD1. Further studies suggested that let-7b-5p can modulate Wnt signaling activity, and the nuclear accumulation of β-catenin was significantly restrained by let-7b-5p through targeting NKD1. Moreover, NKD1 could prohibit the expression of the APC protein. Further studies manifested that NKD1 bound to APC and promoted the ubiquitination degradation of APC through restraining the expression of the deubiquitinating enzyme USP15 and blocking the combination between USP15 and APC. Functionally, NKD1 enhanced the proliferation and migration of colon cancer cells by inhibiting APC expression. This research revealed a novel mechanism by which the let-7b-5p-NKD1-APC-β-catenin signaling pathway inhibited colon cancer cell progression.

Analysis of Differential Expression Profiles of Liver Cancer Cell Proteins After Treatment with Bile Acid

The pathogenesis of liver cancer has not been fully elucidated yet. Bile acids are components of bile, which are inorganic substances and regulate tumor progression. However, the differential expression profile of liver cancer cell proteins after bile acid treatment remains unclear. Human hepatoma cell line SMMC7721 was cultured and randomly assigned into control group and bile acid group followed by measuring the protein expression profile by protein fingerprinting. SMMC7721 cells were transfected with UGT2B or UGT2B, followed by analysis of UGT2B expression, cell proliferation, apoptosis, migration and PI3K/AKT signaling protein expression. The most obvious proteins with an increased expression after bile acid treatment were UGT2B, AAP, APLP2, LAPTM4B, NCOA4 with UGT2B being the most significant one. Overexpression of UGT2B decreased cell proliferation, promoted cell apoptosis, downregulated migration ability and AKT phosphorylation (P <0.05). UGT2B siRNA transfection significantly down-regulated UGT2B expression, promoted cell proliferation, decreased apoptosis rate, increased migration ability and AKT phosphorylation (P <0.05). In conclusion, bile acid can alter the protein expressions of liver cancer cells, with UGT2B being changed most obviously. UGT2B can affect liver cancer cell behaviors via modulating PI3K/AKT signaling.

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control

Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context.

Analysis of C-X-C motif chemokine receptors in breast cancer: potential value in immunotherapy and prognostic prediction.

The concept of individualized therapy has advanced the development of prognostic biomarkers to manage patients with breast cancer (BRCA). Immunotherapy has shown great potential in treating BRCA, and the C-X-C motif chemokine receptor (CXCR) has generated interest in regulating tumor progression through the immune microenvironment. Although CXCRs were utilized for prognosis prediction in glioma with favourable capability, the prognostic and therapeutic role of CXCR in BRCA is unclear. We used The Cancer Genome Atlas (TCGA) database to analyze 1,095 BRCA patients' transcription, mutation, survival time and survival status. Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE), Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), quanTIseq, and Estimating the Proportion of Immune and Cancer cells (EPIC) algorithms were performed to infer the association of CXCR genes with immune cells. We randomly divided the TCGA dataset into a training set and a validation set according to 1:1, constructed a LASSO Cox regression model based on CXCR family genes using the glmnet R package in the training set, assembled clinical variables to draw a visual Nomogram using the R package rms, and validated the model by receiver operating characteristic (ROC) curves, calibration curves with clinical decision curves in the validation set efficacy. Compared to normal samples, CXCR3/4/5 messenger RNA (mRNA) expression levels were upregulated in BRCA samples, whereas CXCR1/2 mRNA expression levels were downregulated. High CXCR3/5/6 expression was associated with a good prognosis. Subsequently, we divided the CXCRs into 2 molecular subgroups based on their expression patterns and explored prognosis, immune infiltration, functional enrichment, hallmarks, and immune response differentiation between the two subgroups. After LASSO Cox regression modeling, a CXCR score predicting overall survival (OS) was constructed, and the predictive accuracy was assessed. By pooling clinical variables, a nomogram individual risk assessment method was established to measure the identification of genuinely high-risk patients who should receive interventions. In summary, CXCR genes were associated with immune infiltration and survival in BRCA patients, and our CXCR-based prognostic model could better predict the prognosis of BRCA patients and provide potential immunotherapy targets for clinical purposes.

Glycine Decarboxylase Suppresses the Renal Cell Carcinoma Growth and Regulates Its Gene Expressions and Functions.

Glycine decarboxylase (GLDC), a key metabolic enzyme, participates in the regulation of the glycine metabolic pathway. Differential expression of GLDC is linked to the malignant growth of renal cell carcinoma (RCC) and may regulate tumor progression through other genes. However, the regulatory function of GLDC in RCC is currently unknown. The purpose of this work was to evaluate the roles of GLDC in the invasion, proliferation, and migration of RCC cells and elucidate the processes underlying RCC development. The expression of GLDC in RCC cell lines and tissues was identified by quantitative reverse transcription polymerase chain reaction (PCR) and western blot. A stably transfected cell line overexpressing GLDC was constructed using a lentiviral vector. Cell proliferation was detected using Cell Counting Kit-8 (CCK8) and EdU experiments, and scratch and transwell assays were used to determine migration and invasion capabilities. Furthermore, differential proteins were identified and obtained using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) analysis. Finally, these differential proteins were analyzed by bioinformatics, including cluster analysis, subcellular localization, domain annotation, annotation of the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), enrichment analysis, and study of protein-protein interactions. GLDC expression was found to be lower in six RCC cell lines (786-O, A498, Caki-1, 769-P, OSRC-2, and ACHN) than in 293T cells and decreased in kidney cancer tissues compared to neighboring normal tissues. Overexpression of GLDC inhibited the proliferation of RCC cells as well as their migration and invasion abilities. Tandem mass tag analysis showed that 317 and 236 genes were downregulated and upregulated, respectively, when GLDC was overexpressed in A498 cells. Tandem mass tag analysis showed that 317 and 236 genes were downregulated and upregulated, respectively, when GLDC was overexpressed in A498 cells. Volcano plot showed these upregulated and downregulated proteins. Cluster analysis showed that differentially expressed protein screening can represent the effect of biological treatment on samples. Subcellular localization analysis showed differential proteins are mainly distributed in the nucleus, cytoplasm, mitochondria, plasma membrane, extracellular matrix, and lysosome. GO annotation showed many biological processes in the cells were changed, including "positive regulation of histone H3-K4 methylation", "cofactor binding", and "nuclear body". KEGG pathway analysis showed key pathways have all undergone considerable alterations, such as "cell cycle", "glyoxylate and dicarboxylate metabolism", and "threonine, glycine, and serine metabolism". Finally, highly aggregated proteins with the same or similar functions were acquired by analysis of the protein-protein interaction (PPI) network. These studies indicate that GLDC overexpression suppresses the invasion, proliferation, and migration of RCC cells and leads to the upregulation and downregulation of 236 and 317 genes, respectively.

LINC00491 Facilitates Tumor Progression of Lung Adenocarcinoma via Wnt/β-Catenin-Signaling Pathway by Regulating MTSS1 Ubiquitination

Background: Long non-coding RNAs have been reported to be involved in tumorigenesis and progression through different regulatory mechanisms. It has been reported that aberrantly expressed long non-coding RNA LINC00491 promotes malignancy in multiple tumors, while the role of LINC00491 in lung adenocarcinoma (LUAD) is little reported and the mechanism for regulating tumor progression has not been elucidated. Methods: RNA sequencing and the TCGA database were combined to screen differentially expressed lncRNAs that facilitate tumor progression. The expression level of LINC00491 was examined in LUAD clinical samples and in cell lines using RT-qPCR. In vitro experiments including colony formation assay, EdU assay, cell migration and invasion assay and wound healing assay, and in vivo experiments including xenografting subcutaneous tumors and lung metastasis models were performed to investigate the function of LINC00491 in LUAD tumor progressions. RNA pull-down, mass spectrometry, RIP assays and truncation experiments were carried out to explore the proteins binding to LINC00491 and the specific interactions between the RNA-protein complex. Results: Our results showed that LINC0491 was significantly upregulated in LUAD and positively correlated with poor survival. High LINC00491 expression promoted proliferation, migration and invasion, and resulted in a high metastatic burden in LUAD. Using pull-down assay and mass spectrometry, MTSS1 was found binding to LINC00491, and the conducted experiments verified the direct interaction between LINC00491 and MTSS1. Meanwhile, LINC00491 was found to regulate MTSS1 degradation by promoting the MTSS1 ubiquitination level and then activating the Wnt/β-catenin-signaling pathway. LINC00491/MTSS1/β-catenin may act as a complex to facilitate tumor progression. Conclusions: In summary, our results found a novel mechanism in which LINC00491 directly interacts with MTSS1 by affecting its ubiquitination modification to promote LUAD proliferation, migration and invasion, then activating the Wnt/β-catenin-signaling pathway, demonstrating its significant role in tumor progression and suggesting that the LINC00491/MTSS1/Wnt/β-catenin-signaling pathway could serve as a potential therapeutic target for lung adenocarcinoma in the future.

TRF-3013b inhibits gallbladder cancer proliferation by targeting TPRG1L

BackgroundtRNA-derived fragments (tRFs) are newly discovered noncoding RNAs and regulate tumor progression via diverse molecular mechanisms. However, the expression and biofunction of tRFs in gallbladder cancer (GBC) have not been reported yet.MethodsThe expression of tRFs in GBC was detected by tRF and tiRNA sequencing in GBC tissues and adjacent tissues. The biological function of tRFs was investigated by cell proliferation assay, clonal formation assay, cell cycle assay, and xenotransplantation model in GBC cell lines. The molecular mechanism was discovered and verified by transcriptome sequencing, fluorescence in situ hybridization (FISH), target gene site prediction, and RNA binding protein immunoprecipitation (RIP).ResultstRF-3013b was significantly downregulated in GBC compared with para-cancer tissues. Decreased expression of tRF-3013b in GBC patients was correlated with poor overall survival. Dicer regulated the production of tRF-3013b, and its expression was positively correlated with tRF-3013b in GBC tissues. Functional experiments demonstrated that tRF-3013b inhibited GBC cell proliferation and induced cell-cycle arrest. Mechanically, tRF-3013b exerted RNA silencing effect on TPRG1L by binding to AGO3, and then inhibited NF-κB. TPRG1L overexpression could rescue the effects of tRF-3013b on GBC cell proliferation.ConclusionsThis study indicated that Dicer-induced tRF-3013b inhibited GBC proliferation by targeting TPRG1L and repressed NF-κB, pointing to tRF-3013b as a novel potential therapeutic target of GBC.

Abstract C074: Mining the secreted microproteome for novel regulators of PDAC progression

Abstract Recent work has unveiled a hidden microproteome composed by thousands of small proteins named microproteins: they are functional short proteins coded by genomic regions previously considered non-coding, and which had been completely ignored, mainly due to their small size (<100 aminoacids). To date, only a small part of the thousands of microproteins present in our cells have been characterized, and they are key players in fundamental processes such as DNA repair, mRNA splicing or cell metabolism. In cancer, they have been shown to regulate most tumor hallmarks, and present a huge potential for the clinic as diagnostic and prognostic biomarkers as well as therapeutic targets. Interestingly, their small size makes them ideal candidates to be shed in tumor-derived exosomes. PDAC-shed exosomes have been shown to prepare the pre-metastatic niche in the liver, and their presence in the bloodstream can be used as a surrogate marker of metastasis. Herein, we have mined the PDAC exosome-secreted microproteome for novel regulators of tumor progression and metastasis. Using proteogenomics in PDAC patient-derived explants, we have identified 439 microproteins secreted in exosomes by pancreatic tumors. We have selected a set of top microprotein candidates for further characterization by in silico analyses (e.g. phylogenetic conservation, predicted protein stability and localisation, mRNA expression in PDAC, etc). We have confirmed their exosome secretion in PDAC cell lines, and preliminary characterisation of these top candidates has shown that they extrinsically promote PDAC cell growth and invasion in vitro. Together, this work advances our knowledge on the underexplored field of secreted microproteins and provides pioneering evidence of their role in tumor cell communication in PDAC. It may further be a source of novel therapeutic targets and PDAC biomarkers for liquid biopsy in the clinic. Citation Format: Marion Martinez, Marta Hergueta, Pilar Ximénez de Embún, Ana Dueso, David Torrents, Teresa Macarulla, Javier Muñoz, Héctor Peinado, María Abad. Mining the secreted microproteome for novel regulators of PDAC progression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C074.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Harnessing Normal and Engineered Mesenchymal Stem Cells Derived Exosomes for Cancer Therapy: Opportunity and Challenges.

There remains a vital necessity for new therapeutic approaches to combat metastatic cancers, which cause globally over 8 million deaths per year. Mesenchymal stem cells (MSCs) display aptitude as new therapeutic choices for cancer treatment. Exosomes, the most important mediator of MSCs, regulate tumor progression. The potential of harnessing exosomes from MSCs (MSCs-Exo) in cancer therapy is now being documented. MSCs-Exo can promote tumor progression by affecting tumor growth, metastasis, immunity, angiogenesis, and drug resistance. However, contradictory evidence has suggested that MSCs-Exo suppress tumors through several mechanisms. Therefore, the exact association between MSCs-Exo and tumors remains controversial. Accordingly, the applications of MSCs-Exo as novel drug delivery systems and standalone therapeutics are being extensively explored. In addition, engineering MSCs-Exo for targeting tumor cells has opened a new avenue for improving the efficiency of antitumor therapy. However, effective implementation in the clinical trials will need the establishment of standards for MSCs-Exo isolation and characterization as well as loading and engineering methods. The studies outlined in this review highlight the pivotal roles of MSCs-Exo in tumor progression and the promising potential of MSCs-Exo as therapeutic drug delivery vehicles for cancer treatment.

The association between genetic variation rs2292832 and the processing efficiency of pre-mir-149 affects the risk of breast cancer.

microRNAs (miRNAs) play key roles in regulating cancer development, including breast cancer. Variation in miRNA genes can associate with the risk of cancer by alterations in the miRNA's processing and maturation. Therefore, human blood samples and breast cancer cell line (MCF7) were analyzed to study any possible association between the genetic variant (rs2292832) in the miR-149 precursor and breast cancer susceptibility. To study the role of rs2292832 polymorphism in breast cancer, the miR-149 gene variant was genotyped using PCR-RFLP. For evaluating the effect of SNP on function and expression levels of mature miR-149, we inserted pre-miR-149 and flanking region with CC or TT genotype into a pEGFPN1 expression vector, and qPCR was accomplished. Cell survival, proliferation, and migration properties investigated by MTT and wound healing assay. Statistical analysis was carried out for data analysis. T allele in variant rs2292832 is associated with an increased risk of breast cancer. Such association was also obtained in co-dominant (OR = 2.5) and dominant (OR = 2.016) models. The variant allele led to reduced production of mature miR-149 and resulted in increased cell proliferation and migration of MCF7 cells. These findings suggest that miR-149 suppresses tumor cell proliferation, and the pre-mir-149 polymorphism affects the processing of miR-149, causing an alteration in the abundance of the miRNA mature form, which can regulate tumor progression and metastasis.

The role of costimulatory molecules in glioma biology and immune microenvironment.

Background: Extensive research showed costimulatory molecules regulate tumor progression. Nevertheless, a small amount of literature has concentrated on the potential prognostic and therapeutic effects of costimulatory molecules in patients with glioma. Methods: The data were downloaded from The Cancer Genome Atlas (TCGA) database, Chinese Glioma Genome Atlas (CGGA) database, and Gene Expression Omnibus (GEO) database for bioinformatics analysis. R software was applied for statistical analysis. Using the FigureYa and Xiantao online tools (https://www.xiantao.love/) for mapping. Results: The Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were utilized to identify the signature consisting of five costimulatory molecules. Multivariate regression analysis revealed that the prognosis of glioma could be independently predicted by the riskscore. Furthermore, we explored clinical and genomic feature differences between the two groups. The level of tumor mutational burden (TMB) was higher in the high-risk group, while more mutation of IDH1 was observed in the low-risk group. Results of Tumor Immune Dysfunction and Exclusion (TIDE) analysis showed that high-risk patients were more prone to be responded to immunotherapy. In addition, subclass mapping analysis was performed to validate our findings and the results revealed that a significantly higher percentage of immunotherapy response rate was observed in the high-risk group. Conclusion: A novel signature with a good independent predictive capacity of prognosis was successfully identified. And our findings reveal that patients with high-risk scores were more likely to be responded to immunotherapy.

Exosome Secretion and Epithelial-Mesenchymal Transition in Ovarian Cancer Are Regulated by Phospholipase D.

Phospholipase D (PLD) isoenzymes participate in a variety of cellular functions that are mostly attributed to phosphatidic acid (PA) synthesis. Dysregulation of PLD regulates tumor progression and metastasis, yet little is known about the underlying mechanism. We previously reported on the expression and clinical role of the PLD isoenzymes PLD1 and PLD2 in tubo-ovarian high-grade serous carcinoma (HGSC). In the present study, we investigated the biological function of PLD1 and PLD2 using the OVCAR-3 and OVCAR-8 HGSC cell lines. KO cell lines for both PLDs were generated using CRISPR/CAS9 technology and assayed for exosome secretion, spheroid formation, migration, invasion and expression of molecules involved in epithelial-mesenchymal transition (EMT) and intracellular signaling. Significant differences between PLD1 and PLD2 KO cells and controls were observed for all the above parameters, supporting an important role for PLD in regulating migration, invasion, metastasis and EMT.

Crosstalk between Tumor-Associated Macrophages and MicroRNAs: A Key Role in Tumor Microenvironment.

As an in-depth understanding of immunotherapy continues to grow, current anticancer therapy research is increasingly focused on the tumor microenvironment (TME). MicroRNAs (miRNAs) play crucial roles in the regulation of genetic information and expression and mediate interactions between tumor cells and components in the TME, such as tumor-associated macrophages (macrophages). Macrophages are abundant in the TME, and their different polarization directions can promote or inhibit tumor growth and progression. By regulating biological behaviors, such as macrophage recruitment, infiltration, and polarization, miRNAs can affect various molecular pathways to regulate tumor progression and treatment response. In this review, we discuss in detail the effects of macrophages on tumors and the multifaceted effects of miRNAs on macrophages. We also discuss the potential clinical applications and prospects of targeted therapy based on miRNAs, novel clinical biomarkers, and drug delivery systems.

Knockdown of growth differentiation factor-15 inhibited nonsmall cell lung cancer through inactivating PTEN/PI3K/AKT signaling pathway.

Non-small cell lung cancer (NSCLC) is characterized by high morbidity and mortality in the world. Growth and differentiation factor 15 (GDF15) has been proved to play an important role in regulating tumor progression. However, the influence of GDF15 on NSCLC remains unclear. We aimed to investigate the regulatory role of GDF15 in NSCLC. The correlation between GDF15 expression and prognosis, stage of NSCLC was examined with bioinformatics method. The cell proliferation was detected with CCK8 and EdU staining. Wound healing, Transwell, flow cytometry assays were used to measure cell migration, invasion, and apoptosis, respectively. High expression of GDF15 is correlated with worse survival and malignant progression of NSCLC. Knockdown of GDF15 restrained the proliferation, invasion, migration, but accelerated apoptosis of lung cancer cells through regulating PTEN/PI3K/AKT signaling pathway. sh-GDF15 suppressed epithelial mesenchymal transition (EMT) process and promoted the chemotherapy sensitivity of lung cancer cells. GDF15 plays an important role in NSCLC progression. GDF15 mediated PTEN/PI3K/AKT signaling pathway might be the potential therapeutic targets for the prevention and treatment of GDF15.

Excessive HSP70/TLR2 activation leads to remodeling of the tumor immune microenvironment to resist chemotherapy sensitivity of mFOLFOX in colorectal cancer

For locally advanced colorectal cancer (CRC), neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision or complete mesocolic excision is the standard therapeutic strategy, which is key to patient survival. Involvement of the tumor immune microenvironment is a factor that regulates tumor progression and sensitivity to nCRT in CRC. In this study, we aimed to identify the effect of heat-shock protein 70 (HSP70)/toll-like receptor-2 (TLR-2) on mFOLFOX sensitization for CRC. A total of 22 patients with advanced CRC who had received neoadjuvant mFOLFOX were enrolled and classified into the mFOLFOX-insensitive or -sensitive group, according to the tumor regression grade. The abundance of immune infiltrates was significantly higher in the post-operative pathological specimens of the mFOLFOX-insensitive group, as compared to those of the mFOLFOX-sensitive group. After transcriptome sequencing, differentially expressed genes between the two groups were annotated to inflammatory and immune responses using Gene Ontology (GO) analysis, and the TLR signaling pathway was analyzed using Kyoto Encyclopedia of Genes and Genomes pathway analysis. Significantly higher expression levels of HSP60, HSP70, HSP90, and TLR-2 in the mFOLFOX-insensitive group were detected using immunofluorescence assays. TIMER2.0 platform was introduced to further narrow the scope of HSP70 (HSPA6 or HSPA7) and TLR-2, which exhibited positive correlations with dendritic cells, Tregs, or CD4+ T cells and negative correlations with CD3+ or CD8+ T cells, implying that HSP70/TLR-2 activation mediates immunosuppressive cells to counteract CD8+ T cells, which may be a novel target of CRC treatment. A promising synergistic effect of mFOLFOX combined with a TLR-2 inhibitor was observed in vivo in mouse allograft models, which could be partly rescued by recombinant HSP70 protein. Immunohistochemical staining of allografts and immunofluorescence assays of clinical specimens corroborated the regulatory effects of the immune microenvironment. In summary, HSP70/TLR-2 activation can regulate the tumor immune microenvironment of CRC and further remodel its sensitivity to mFOLFOX. However, the specific mechanisms remain unclear and require further investigation. This study is expected to provide a new direction for the clinical treatment of CRC.

Circ_0002111/miR-134-5p/FSTL1 signal axis regulates tumor progression and glycolytic metabolism in papillary thyroid carcinoma cells.

Circular RNAs (circRNAs) have essential roles in the malignant progression of papillary thyroid carcinoma (PTC). Circ_0002111 was reported to facilitate cell proliferation and invasion abilities in PTC. This study was performed to explore the regulatory mechanism of circ_0002111 in PTC progression. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used for the level detection of circ_0002111, microRNA-134-5p (miR-134-5p) and Follistatin Like 1 (FSTL1). Cell proliferation was assessed by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) assay, EdU assay and colony formation assay. Cell migration ability was determined by transwell assay. Glycolysis was analyzed by extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose consumption and lactate production. The protein quantification was performed through western blot. Xenograft tumor assay was used for the functional analysis of circ_0002111 in vivo. The target interaction was confirmed by dual-luciferase reporter assay and RNA pull-down assay. The significant upregulation of circ_0002111 was detected in PTC samples and cells. PTC cell proliferation, migration and glycolytic metabolism were suppressed after circ_0002111 downregulation. PTC tumorigenesis in vivo was also inhibited by circ_0002111 knockdown. In addition, circ_0002111 could target miR-134-5p and si-circ_0002111#1-induced inhibition of PTC progression was relieved by miR-134-5p expression downregulation. Furthermore, FSTL1 was a target gene for miR-134-5p and miR-134-5p served as a tumor repressor in PTC by targeting FSTL1. Moreover, circ_0002111 could increase the FSTL1 level via sponging miR-134-5p. All results indicated that circ_0002111 promoted the malignant behaviors of PTC cells partly by regulating the miR-134-5p/FSTL1 molecular network.