Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAMs in colorectal cancer are contradictory. We therefore investigated the ...functions, mechanisms, and clinical significance of TAMs in colorectal cancer.
We measured the macrophage infiltration (CD68), P-gp, and Bcl2 expression in colorectal cancer tissues using IHC staining. Coculture of TAMs and colorectal cancer cells both
and
models was used to evaluate the effects of TAMs on colorectal cancer chemoresistance. Cytokine antibody arrays, ELISA, neutralizing antibody, and luciferase reporter assay were performed to uncover the underlying mechanism.
TAM infiltration was associated with chemoresistance in patients with colorectal cancer. Colorectal cancer-conditioned macrophages increased colorectal cancer chemoresistance and reduced drug-induced apoptosis by secreting IL6, which could be blocked by a neutralizing anti-IL6 antibody. Macrophage-derived IL6 activated the IL6R/STAT3 pathway in colorectal cancer cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced colorectal cancer chemoresistance. miR-155-5p, a key miRNA regulating C/EBPβ, was frequently downregulated in TAMs, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL6 in TAMs, and TAM-secreted IL6 then induced chemoresistance by activating the IL6R/STAT3/miR-204-5p pathway in colorectal cancer cells.
Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL6 signaling in TAMs could induce chemoresistance in colorectal cancer cells by regulating the IL6R/STAT3/miR-204-5p axis, revealing a new cross-talk between immune cells and tumor cells in colorectal cancer microenvironment.
.
Recent preliminary studies reported the in vitro tumor-promoting effects of long non-coding RNA urothelial carcinoma associated 1 (UCA1) in colorectal cancer (CRC). However, the in vivo functions and ...molecular mechanism of UCA1 in CRC remain unclear. Therefore, we investigated the detailed role and mechanism of UCA1 in CRC. We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Functional assays revealed the in vitro and in vivo growth-promoting function of UCA1 and revealed that UCA1 can decrease the sensitivity of CRC cells to 5-FU by attenuating apoptosis. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.
Background
Chemoresistance is a common problem for cancer treatment worldwide. Circulating exosomal microRNAs (miRNAs) have been considered as promising biomarkers of cancers. However, few studies ...have assessed the relationship between serum/plasma exosomal microRNAs and chemoresistance in colorectal cancer (CRC).
Methods
Based on previous microarray analysis, we selected 30 miRNAs which are aberrantly expressed during CRC progression and then detected their expression levels in three pairs of oxaliplatin/5-fluorouracil-resistant CRC cell lines and the corresponding secreted exosomes. Six candidate exosomal miRNAs were identified for further evaluating potential value in predicting chemotherapeutic effect in advanced CRC patients. Finally, the molecular mechanisms of these miRNAs in drug resistance were explored by bioinformatics preliminarily.
Results
We observed that the expression of 14 miRNAs was significantly higher in three drug-resistant CRC cells comparing with their parental cells. Among these miRNAs, miR-21-5p, miR-1246, miR-1229-5p, miR-135b, miR-425 and miR-96-5p are also up-regulated in exosomes from culture media of resistant cells. Clinical sample analysis confirmed that the expression levels of miR-21-5p, miR-1246, miR-1229-5p and miR-96-5p in serum exosomes were significantly higher in chemoresistant patients in contrast with chemosensitive controls. ROC curve showed that the combination of the four miRNAs had an area of under the curve (AUC) of 0.804 (
P
< 0.05). In addition, GO analysis and KEGG pathway analysis revealed that these miRNAs were enriched in PI3K-Akt signaling pathway, FoxO signaling pathway and autophagy pathway.
Conclusions
Our study demonstrates that a panel of serum exosomal miRNAs containing miR-21-5p, miR-1246, miR-1229-5p and miR-96-5p could significantly distinguish the chemotherapy-resistant group from advanced colorectal cancer patients. Targeting these miRNAs may promote chemosensitivity to oxaliplatin and 5-fluorouracil, and might be promising strategy for CRC treatment.
miR-204-5p was found to be downregulated in colorectal cancer tissues in our preliminary microarray analyses. However, the function of miR-204-5p in colorectal cancer remains unknown. We therefore ...investigated the role, mechanism, and clinical significance of miR-204-5p in colorectal cancer development and progression.
We measured the expression of miR-204-5p and determined its correlation with patient prognoses. Ectopic expression in colorectal cancer cells, xenografts, and pulmonary metastasis models was used to evaluate the effects of miR-204-5p on proliferation, migration, and chemotherapy sensitivity. Luciferase assay and Western blotting were performed to validate the potential targets of miR-204-5p after the preliminary screening by a microarray analysis and computer-aided algorithms.
miR-204-5p is frequently downregulated in colorectal cancer tissues, and survival analysis showed that the downregulation of miR-204-5p in colorectal cancer was associated with poor prognoses. Ectopic miR-204-5p expression repressed colorectal cancer cell growth both in vitro and in vivo. Moreover, restoring miR-204-5p expression inhibited colorectal cancer migration and invasion and promoted tumor sensitivity to chemotherapy. Mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in colorectal cancer. Furthermore, RAB22A protein levels in colorectal cancer tissues were frequently increased and negatively associated with miR-204-5p levels and survival time.
Our results demonstrate for the first time that miR-204-5p acts as a tumor suppressor in colorectal cancer through inhibiting RAB22A and reveal RAB22A to be a new oncogene and prognostic factor for colorectal cancer.
The increasing maturity of sequencing technology provides a convenient approach to studying the role of skin microorganisms in acne pathogenesis. However, there are still too few studies about the ...skin microbiota of Asian acne patients, especially a lack of detailed analysis of the characteristics of the skin microbiota in the different acne sites.
In this study, a total of 34 college students were recruited and divided into the health, mild acne, and severe acne groups. The bacterial and fungal flora of samples were separately detected by 16S and 18S rRNA gene sequencing. The biomarkers of different acne grades and different acne sites forehead, cheek, chin, torso (including chest and back) were excavated.
Our results indicated that there was no significant difference in species diversity between groups. The genera like
, and
, which have a relatively high abundance in the skin microbiota and were reported as the most acne-associated microbes, were no obvious differences between groups. On the contrary, the abundance of less reported Gram-negative bacteria (
,
,
) and
has a significant alteration. Compared with the health group and the mild group, in the severe group, the abundance of
and
sharply reduced while that of
and
remarkably raised. Moreover, different acne sites have different numbers and types of biomarkers. Among the four acne sites, the cheek has the greatest number of biomarkers including
,
,
,
,
, and
, while no biomarker was observed for the forehead. The network analysis indicated that there might be a competitive relationship between
and
. This study would provide a new insight and theoretical basis for precise and personalized acne microbial therapy.
SLCO4A1-AS1 was found to be upregulated in several cancer types, including colorectal cancer (CRC). However, the detailed roles of SLCO4A1-AS1 in CRC remain to be elucidated. Therefore, we ...investigated the functions, mechanism, and clinical significance of SLCO4A1-AS1 in colorectal tumourigenesis.
We measured the expression of SLCO4A1-AS1 in CRC tissues using qRT-PCR and determined its correlation with patient prognosis. Promoter methylation analyses were used to assess the methylation status of SLCO4A1-AS1. Gain- and loss-of-function assays were used to evaluate the effects of SLCO4A1-AS1 on CRC growth in vitro and in vivo. RNA pull-down, RNA immunoprecipitation, RNA-seq, luciferase reporter and immunohistochemistry assays were performed to identify the molecular mechanism of SLCO4A1-AS1 in CRC.
SLCO4A1-AS1 was frequently upregulated in CRC tissues based on multiple CRC cohorts and was associated with poor prognoses. Aberrant overexpression of SLCO4A1-AS1 in CRC is partly attributed to the DNA hypomethylation of its promoter. Ectopic SLCO4A1-AS1 expression promoted CRC cell growth, whereas SLCO4A1-AS1 knockdown repressed CRC proliferation both in vitro and in vivo. Mechanistic investigations revealed that SLCO4A1-AS1 functions as a molecular scaffold to strengthen the interaction between Hsp90 and Cdk2, promoting the protein stability of Cdk2. The SLCO4A1-AS1-induced increase in Cdk2 levels activates the c-Myc signalling pathway by promoting the phosphorylation of c-Myc at Ser62, resulting in increased tumour growth.
Our data demonstrate that SLCO4A1-AS1 acts as an oncogene in CRC by regulating the Hsp90/Cdk2/c-Myc axis, supporting SLCO4A1-AS1 as a potential therapeutic target and prognostic factor for CRC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Radiotherapy (RT) represents one of the major treatment methods for cancers. However, many studies have observed that in descendant surviving tumor cells, sublethal irradiation can promote metastatic ...ability, which is closely related to the tumor microenvironment. We therefore investigated the functions and mechanisms of sublethal irradiated liver nonparenchymal cells (NPCs) in hepatocellular carcinoma (HCC). In this study, primary rat NPCs and McA‐RH7777 hepatoma cells were irradiated with 6 Gy X‐ray. Conditioned media (CM) from nonirradiated (SnonR), irradiated (SR), or irradiated plus radiosensitizer celecoxib‐treated (SR + D) NPCs were collected and added to sublethal irradiated McA‐RH7777 cells. We showed that CM from sublethal irradiated NPCs significantly promoted the migration and invasion ability of sublethal irradiated McA‐RH7777 cells, which was reversed by celecoxib. The differentially expressed genes in differently treated McA‐RH7777 cells were enriched mostly in the AMP‐activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. SR increased the migration and invasion ability of HCC cells by inhibiting AMPK/mTOR signaling, which was enhanced by the AMPK inhibitor compound C and blocked by the AMPK activator GSK‐621. Analyses of HCC tissues after neoadjuvant radiotherapy confirmed the effects of radiation on the AMPK/mTOR pathway. Cytokine antibody arrays and further functional investigations showed that matrix metalloproteinase‐8 (MMP‐8) partly mediates the promotion effects of SR on the migration and invasion ability of HCC cells by regulating AMPK/mTOR signaling. In summary, our data indicate that MMP‐8 secreted by irradiated NPCs enhanced the migration and invasion of HCC by regulating AMPK/mTOR signaling, revealing a novel mechanism mediating sublethal irradiation–induced HCC metastasis at the level of the tumor microenvironment.
In this work, we observed that conditioned media from sublethally irradiated liver nonparenchymal cells (NPCs) promoted the migration and invasion ability of sublethally irradiated McA‐RH7777 hepatoma cells. Further mechanistic studies revealed that matrix metalloproteinase‐8 (MMP‐8) secreted by NPCs enhanced the migration and invasion of hepatocellular carcinoma (HCC) by regulating the AMPK/mTOR signaling pathway. These findings might offer a new strategy for improving the therapeutic effect of radiotherapy.
We propose a new model to identify epilepsy EEG signals. Some existing intelligent recognition technologies require that the training set and test set have the same distribution when recognizing EEG ...signals, some only consider reducing the marginal distribution distance of the data while ignoring the intra-class information of data, and some lack of interpretability. To address these deficiencies, we construct a TSK transfer learning fuzzy system (TSK-TL) based on the easy-to-interpret TSK fuzzy system the transfer learning method. The proposed model is interpretable. By using the information contained in the source domain and target domains more effectively, the requirements for data distribution are further relaxed. It realizes the identification of epilepsy EEG signals in data drift scene. The experimental results show that compared with the existing algorithms, TSK-TL has better performance in EEG recognition of epilepsy.
A tertiary lymphoid structure (TLS) refers to an organized infiltration of immune cells that is linked to a positive prognosis and improved response to immunotherapy. However, methods that promote ...TLS formation are limited and challenging to implement in clinical settings. In this study, we aimed to promote the formation and maturation of TLSs in lung adenocarcinoma (LUAD) by combining low-dose radiotherapy (LDRT) with immunotherapy.
Tissue sections from 198 patients who had undergone surgery were examined. Risk factors for patient survival were assessed, and the relationship between TLSs and five-year survival was analyzed. The Kras-LSL-G12D spontaneous lung cancer mouse model was used to screen the optimal irradiation dose (0/1/2 Gy whole lung irradiation) for promoting TLS formation. LDRT combined with anti-PD-1 was used to promote the formation and maturation of TLSs.
TLS+, TLS
, TLS+GC+ and CD8
within TLS+ were associated with a favorable prognosis. LDRT increased the formation of early TLSs in the Kras-LSL-G12D lung cancer mouse model. In addition, LDRT combined with anti-PD-1 treatment can significantly improve the maturity of TLSs in mouse LUAD, resulting in greater antitumor effects. This antitumor effect was strongly associated with the number of CD8+ T cells within the TLSs.
We successfully applied LDRT combined with PD-1 inhibitor therapy for the first time, which increased both the quantity and maturity of TLSs in lung cancer. This approach achieved a promising antitumor effect.
Tumor‐associated macrophages (TAMs) are one of the most abundant cell types in colorectal cancer (CRC) tumor microenvironment (TME). Recent studies observed complicated “cross‐talks” between cancer ...cells and macrophages in TME. However, the underlying mechanisms are still poorly elucidated. Here, PD‐L1 levels are very low in CRC cells but highly abundant in TAMs, and a specific PD‐L1+CD206+ macrophage subpopulation are identified, which is induced by tumor cells and associated with a poor prognosis. Mechanistic investigations reveal that CRC cells can secrete small extracellular vesicles (sEVs) taken up by macrophages that induce M2 like polarization and PD‐L1 expression, resulting in increased PD‐L1+CD206+ macrophage abundance and decreased T cell activity in CRC TME. sEV‐derived miR‐21‐5p and miR‐200a are identified as key signaling molecules mediating the regulatory effects of CRC on macrophages. Further studies reveal that CRC‐derived miR‐21‐5p and miR‐200a synergistically induces macrophage M2 like polarization and PD‐L1 expression by regulating the PTEN/AKT and SCOS1/STAT1 pathways, resulting in decreased CD8+ T cell activity and increased tumor growth. This study suggests that inhibiting the secretion of specific sEV‐miRNAs from CRC and targeting PD‐L1 in TAMs may serve as novel methods for CRC treatment as well as a sensitization method for anti‐PD‐L1 therapy in CRC.
A specific PD‐L1+CD206+ macrophage risk subgroup is identified in colorectal cancer, which is induced by tumor‐derived sEV‐miRNAs. This subgroup promotes tumor growth by inducing an immunosuppressive tumor microenvironment. Hence, targeting specific tumor sEV‐miRNAs that regulate PD‐L1 in tumor‐associated macrophages may serve as a novel treatment strategy and a sensitization method for anti‐PD‐L1 therapy in colorectal cancer.
PDF
