FOSB, a member of the FOS gene family, forms heterodimers with JUN family proteins to engage in diverse cellular processes. Its biological impacts vary among different types of tumors, yet its specific function in colon cancer (CC) remains ambiguous. In this study, quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) are applied to measure FOSB expression levels, followed by an analysis of the association between FOSB expression and patients' clinical parameters. In vitro experiments are performed to assess cell proliferation, including growth rate, cell cycle distribution, and apoptosis. A subcutaneous xenograft model in nude mice is utilized to monitor tumor growth in vivo. Additionally, chromatin immunoprecipitation (ChIP) and luciferase reporter assays are conducted to dissect the interactions among FOSB, miR-133b, and POU2F1. The results indicate that FOSB expression is downregulated in CC tissues relative to normal controls. Overexpression of FOSB suppresses proliferation and promotes apoptosis in CC cells. Mechanistically, FOSB binds to the promoter region of miR-133b, enhancing its transcription and subsequently repressing POU2F1 expression. Notably, decreased POU2F1 expression also alleviates the transcriptional repression of the FOSB promoter region, establishing a FOSB-miR-133b-POU2F1 feedback loop that inhibits CC proliferation. In summary, our findings suggest that FOSB acts as a tumor suppressor gene in CC and may exert its inhibitory effects on CC growth via the FOSB-miR-133b-POU2F1 feedback loop.

The persistence of high relapse rates and therapy resistance continues to challenge the effective management of multiple myeloma (MM). The identification of novel MM-specific molecular markers could ameliorate risk-stratification tools and accurately identify high-risk patients towards personalized prognosis and therapy. miRNA-seq analysis of CD138+ plasma cells (n = 24) unveiled miR-221-3p and miR-222-3p (miR-221/222 cluster) as the most downregulated miRNAs in R-ISS III compared to R-ISS I/II patients. Subsequently, miR-221/222 levels were quantified by RT-qPCR in CD138+ plasma cells of our screening cohort (n = 141), assessing patients' mortality and disease progression as clinical endpoints. Internal validation was performed by bootstrap analysis, while clinical benefit was estimated by decision curve analysis. Kryukov et al. (n = 149) and Aass et al. (n = 86) served as institutional-independent validation cohorts. Loss of miR-221/222 cluster was strongly associated with patients' short-term progression and poor overall survival, which was confirmed by Kryukov et al. and Aass et al. validation cohorts. Intriguingly, miR-221/222-fitted multivariate models offered superior risk-stratification within R-ISS staging and risk-based cytogenetics. Moreover, miR-221/222 loss could effectively discriminate optimal 1st-line treatment responders with inferior treatment outcome. Our study identified the loss of miR-221/222 cluster as a powerful independent predictor of patients' post-treatment progression, ameliorating prognosis and supporting precision medicine in MM.

Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication in cancer. These membranous structures, secreted by normal and cancerous cells, carry a cargo of bioactive molecules including microRNAs (miRNAs) that modulate various cellular processes. miRNAs are small non-coding RNAs that play pivotal roles in post-transcriptional gene regulation and have been implicated in cancer initiation, progression, and metastasis. In cancer, tumor-derived EVs transport specific miRNAs to recipient cells, modulating tumorigenesis, growth, angiogenesis, and metastasis. Dysregulation of miRNA expression profiles within EVs contributes to the acquisition of cancer hallmarks that include increased proliferation, survival, and migration. EV miRNAs influence the tumor microenvironment, promoting immune evasion, remodeling the extracellular matrix, and establishing pre-metastatic niches. Understanding the complex interplay between EVs, miRNAs, and cancer holds significant promise for developing novel diagnostic and therapeutic strategies. This chapter provides insights into the role of EV-mediated miRNA signaling in cancer pathogenesis, highlighting its potential as a biomarker for cancer detection, prognosis, and treatment response assessment.

Colorectal cancer (CRC) presents ongoing challenges due to limited treatment effectiveness and a discouraging prognosis, underscoring the need for ground-breaking therapeutic approaches. This review delves into the pivotal role of E3 ubiquitin ligases and deubiquitinases (DUBs), underscoring their role as crucial regulators for tumor suppression and oncogenesis in CRC. We spotlight the diverse impact of E3 ligases and DUBs on CRC's biological processes and their remarkable versatility. We closely examine their specific influence on vital signaling pathways, particularly Wnt/β-catenin and NF-κB. Understanding these regulatory mechanisms is crucial for unravelling the complexities of CRC progression. Importantly, we explore the untapped potential of E3 ligases and DUBs as novel CRC treatment targets, discussing aspects that may guide more effective therapeutic strategies. In conclusion, our concise review illuminates the E3 ubiquitin ligases and deubiquitinases pivotal role in CRC, offering insights to inspire innovative approaches for transforming the treatment landscape in CRC.

In this study, we aimed to investigate the regulatory effects of a green tea and java pepper mixture (GTP) on the gut microbiome and microRNA (miR)-221/222 expression in mice with dextran sulfate sodium (DSS)-induced colitis. Male C57BL/6J mice were divided into four groups: DSS-, DSS+, GTP50, and GTP100. In the GTP50 and GTP100 groups, GTP was orally administered to mice at doses of 50 and 100 mg/kg body weight, respectively, every day for 2 weeks, and colitis was induced in the DSS+, GTP50, and GTP100 groups by adding 3% DSS to their drinking water for 1 week. GTP was found to mitigate the severity of inflammation and the damage to goblet cells caused by DSS-induced colitis. The results showed that compared with the DSS- group, the relative abundance of Bacteroidetes was increased and that of Proteobacteria and Candidatus Melainabacteria was decreased in the GTP100 group. The ratio of Firmicutes to Bacteroidetes was also reduced in the GTP100 group. However, GTP administration did not modulate the microbial diversity. GTP administration upregulated the mRNA and protein levels of occludin and zonula occludens 1. In addition, GTP effectively downregulated the expression of miR-221 and miR-222. Overall, GTP altered the gut microbiota composition and downregulated colonic miR-221/222 expression in mice with DSS-induced colitis.

Oxidative stress is crucial in ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC). Intestinal epithelial cells (IECs) are an important component of the intestinal barrier. In previous studies, we have demonstrated that suppressing microRNA-222-3p (miR-222-3p) can protect against oxidative stress in IECs, which ameliorates colonic injuries in UC mice and prevents the conversion of UC to CAC. In this case, we hope to explore whether moxibustion can alleviate UC and CAC by inhibiting miR-222-3p based on mouse models of UC and CAC. After herb-partitioned moxibustion (HPM) intervention, the disease activity index (DAI) and colon macroscopic damage index (CMDI) were significantly reduced in UC mice, and the number and volume of intestinal tumors were decreased considerably in CAC mice. Meanwhile, we found that HPM suppressed miR-222-3p expression and upregulated the mRNA and protein expression of Brahma-related gene 1 (BRG1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), while inhibiting Kelch-like ECH-associated protein 1 (Keap1) expression in IECs of UC and CAC mice. With changes in reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α), we verified that HPM protects against oxidative stress and inflammation in IECs of UC and CAC mice. The effect of HPM was inhibited in miR-222-3p overexpression mice, further demonstrating that the protective effect of HPM on UC and CAC mice was through inhibiting miR-222-3p. In summary, HPM regulates the BRG1/Nrf2/HO-1 pathway by inhibiting miR-222-3p to attenuate oxidative stress in IECs in UC and CAC.

Chronic inflammation has been associated with the development of cancer in various anatomical sites. However, the crosstalk between inflammatory factors and circular RNAs (circRNAs) in tumorigenesis is unclear. Here, we revealed that circDMD was upregulated in Tumor necrosis factor alpha-like (TNFα)-induced HeLa cells. circDMD promoted the expression and nuclear translocation of Nuclear factor kappa B subunit (NF-κB) to activate downstream factors. circDMD absorbed miR-4711-5p to increase Lysine demethylase 5 A (KDM5A) expression, which reduced Suppressor of cytokine signaling 1 (SOCS1) to decrease the ubiquitination of Rela proto-oncogene (P65). In addition, circDMD promoted Fms related receptor tyrosine kinase 4 (VEGFR3) expression through the formation of an R-loop in its promoter. circDMD promoted tumor proliferation, metastasis and autophagy by activating the NF-κB pathways in vitro and in tumors derived from HeLa cells in vivo. Taken together, our results indicated that the expression of circDMD is induced by TNFα and contributes to tumorigenesis in cervical cancer (CC), which might help elucidate the regulatory effects of circRNAs on tumorigenesis.

Colorectal cancer (CRC), as the third most common bisexual cancer worldwide, requires urgent research on its underlying mechanisms and intervention methods. NRF2 is an important transcription factor involved in the regulation of redox homeostasis, protein degradation, DNA repair, and other cancer processes, playing an important role in cancer. In recent years, the complex role of NRF2 in CRC has been continuously revealed: on the one hand, it exhibits a chemopreventive effect on cancer by protecting normal cells from oxidative stress, and on the other hand, it also exhibits a protective effect on malignant cells. Therefore, this article explores the dual role of NRF2 and its related signaling pathways in CRC, including their chemical protective properties and promoting effects in the occurrence, development, metastasis, and chemotherapy resistance of CRC. In addition, this article focuses on exploring the regulation of NRF2 in CRC ferroptosis, as well as NRF2 drug modulators (activators and inhibitors) targeting CRC, including natural products, compounds, and traditional Chinese medicine formulations.

Rationally-engineered functional biomaterials offer the opportunity to interface with complex biology in a predictive, precise, yet dynamic way to reprogram their behaviour and correct shortcomings. Success here may lead to a desired therapeutic effect against life-threatening diseases, such as cancer. Here, we engineered "Crab"-like artificial ribonucleases through coupling of peptide and nucleic acid building blocks, capable of operating alongside and synergistically with intracellular enzymes (RNase H and AGO2) for potent destruction of oncogenic microRNAs. "Crab"-like configuration of two catalytic peptides ("pincers") flanking the recognition oligonucleotide was instrumental here in providing increased catalytic turnover, leading to ≈30-fold decrease in miRNA half-life as compared with that for "single-pincer" conjugates. Dynamic modeling of miRNA cleavage illustrated how such design enabled "Crabs" to drive catalytic turnover through simultaneous attacks at different locations of the RNA-DNA heteroduplex, presumably by producing smaller cleavage products and by providing toeholds for competitive displacement by intact miRNA strands. miRNA cleavage at the 5'-site, spreading further into double-stranded region, likely provided a synergy for RNase H1 through demolition of its loading region, thus facilitating enzyme turnover. Such synergy was critical for sustaining persistent disposal of continually-emerging oncogenic miRNAs. A single exposure to the best structural variant (Crab-p-21) prior to transplantation into mice suppressed their malignant properties and reduced primary tumor volume (by 85 %) in MCF-7 murine xenograft models.

To investigate the effect of decarbromodiphenyl ether (BDE-209) exposure on the migration ability of triple-negative breast cancer (TNBC) cells and to explore the underlying mechanism.

Human TNBC MDA-MB-231 cells were divided into blank control group and BDE-209 exposure groups (treated with 0.02, 0.20, 2.00, 20.00 and 200.00 ng/mL BDE-209 in high glucose DMEM). Extracellular vehicles (EVs) secreted by MDA-MB-231 cells were isolated by differential ultracentrifugation. Transmission electron microscopy (SEM), nanoparticle tracking analysis (NTA) and Western blotting were performed to characterize the EVs. The effect of the EVs induced by BDE-209 exposure (EVs-BDE-209) on the migration and invasion of MDA-MB-231 cells was detected by wound-healing assay and Transwell test. qRT-PCR was used to measure the miR-221 level in EVs-BDE-209. The expression of MMP9 in MDA-MB-231 cells was determined by Western blotting.

Compared with the blank control, BDE-209 exposure increased the tumor cell-derived EVs in dose-dependent manner. The MDA-MB-231 cells co-cultured with EVs released by 200.00 ng/mL BDE-209 exposure showed an 86% increase in cell migration rate, a 1.32-fold higher number of membrane-penetrating cells, a 2.71-fold higher expression level of miR-221, and a 1.62-fold higher expression level of MMP9 compared with the blank control group (all P<0.05). While transfection with anti-miR-221 antibody to decrease miR-221 level in EVs significantly reversed the increased invasion ability of the MDA-MB-231 cells treated with EVs-BDE-209.

BDE-209 exposure may promote metastasis potential of MDA-MB-231 cells via EVs-BDE-209 transmitted miR-221.

Organs of future metastasis are not passive receivers of circulating tumor cells, but are instead selectively and actively modified by the primary tumor before metastatic spread has even occurred. Tumors orchestrate a pre-metastatic program by conditioning distant organs to create microenvironments that foster the survival and proliferation of tumor cells before their arrival, thereby establishing pre-metastatic niches. Primary tumor-derived exosomes modulate these pre-metastatic niches, generating a permissive environment that facilitates the homing and expansion of tumor cells. Moreover, microRNAs have emerged as a key component of exosomal cargo, serving not only to induce the formation of pre-metastatic niches but also to prime these sites for the arrival and colonization of specific secondary tumor populations. Against this backdrop, this review endeavors to elucidate the impact of tumor-derived exosomal microRNAs on the genesis of their individualized pre-metastatic niches, with a view towards identifying novel means of specifying cancer metastasis and exploiting this phenomenon for cancer immunotherapy.

The research on the correlation or causality between gut microbiota and the occurrence, development, and treatment of colorectal cancer (CRC) is receiving increasing emphasis. At the same time, the incidence and mortality of colorectal cancer vary among individuals and regions, as does the gut microbiota. In order to gain a better understanding of the characteristics of the gut microbiota in CRC patients and the differences between different regions, we initially compared the gut microbiota of 25 CRC patients and 26 healthy controls in the central region of China (Hubei Province) using 16S rRNA high-throughput sequencing technology. The results showed that Corynebacterium, Enterococcus, Lactobacillus, and Escherichia-Shigella were significantly enriched in CRC patients. In addition, we also compared the potential differences in functional pathways between the CRC group and the healthy control group using PICRUSt's functional prediction analysis. We then analyzed and compared it with five cohort studies from various regions of China, including Central, East, and Northeast China. We found that geographical factors may affect the composition of intestinal microbiota in CRC patients. The composition of intestinal microbiota is crucial information that influences colorectal cancer screening, early detection, and the prediction of CRC treatment outcomes. This emphasizes the importance of conducting research on CRC-related gut microbiota in various regions of China.

Cancer is characterized by dysregulated cellular metabolism. Thus, understanding the mechanisms underlying these metabolic alterations is important for developing targeted therapies. In this study, we investigated the pro-tumoral effect of PDZ and LIM domain 2 (PDLIM2) downregulation in lung cancer growth and its association with the accumulation of mitochondrial ROS, oncometabolites and the activation of hypoxia-inducible factor-1 (HIF-1) α in the process.

Databases and human cancer tissue samples were analyzed to investigate the roles of PDLIM2 and HIF-1α in cancer growth. DNA microarray and gene ontology enrichment analyses were performed to determine the cellular functions of PDLIM2. Seahorse assay, flow cytometric analysis, and confocal microscopic analysis were employed to study mitochondrial functions. Oncometabolites were analyzed using liquid chromatography-mass spectrometry (LC-MS). A Lewis lung carcinoma (LLC) mouse model was established to assess the in vivo function of PDLIM2 and HIF-1α.

The expression of PDLIM2 was downregulated in lung cancer, and this downregulation correlated with poor prognosis in patients. PDLIM2 highly regulated genes associated with mitochondrial functions. Mechanistically, PDLIM2 downregulation resulted in NF-κB activation, impaired expression of tricarboxylic acid (TCA) cycle genes particularly the succinate dehydrogenase (SDH) genes, and mitochondrial dysfunction. This disturbance contributed to the accumulation of succinate and other oncometabolites, as well as the buildup of mitochondrial reactive oxygen species (mtROS), leading to the activation of hypoxia-inducible factor 1α (HIF-1α). Furthermore, the expression of HIF-1α was increased in all stages of lung cancer. The expression of PDLIM2 and HIF-1α was reversely correlated in lung cancer patients. In the animal study, the orally administered HIF-1α inhibitor, PX-478, significantly reduces PDLIM2 knockdown-promoted tumor growth.

These findings shed light on the complex action of PDLIM2 on mitochondria and HIF-1α activities in lung cancer, emphasizing the role of HIF-1α in the tumor-promoting effect of PDLIM2 downregulation. Additionally, they provide new insights into a strategy for precise targeted treatment by suggesting that HIF-1α inhibitors may serve as therapy for lung cancer patients with PDLIM2 downregulation.

Colorectal cancer (CRC) is one of the most common malignancies and a relevant cause of cancer-related deaths worldwide. Dysregulation of microRNA (miRNA) expression has been associated with the development and progression of various cancers, including CRC. Among them, miR-221 emerged as an oncogenic driver, whose high expression is associated with poor patient prognosis. The present study was conceived to investigate the anti-CRC activity of miR-221 silencing based on early clinical data achieved from a first-in-human study by our group. Going back from bedside to bench, we demonstrated that LNA-i-miR-221 reduces cell viability, induces apoptosis in vitro, and impairs tumor growth in preclinical in vivo models of CRC. Importantly, we disclosed that miR-221 directly targets TP53BP2, which, together with TP53INP1, is known as a positive regulator of the TP53 apoptotic pathway. We found that (1) both these genes are overexpressed following miR-221 inhibition, (2) the strong anti-tumor activity of LNA-i-miR-221 was selectively observed on TP53 wild-type cells, and (3) this activity was reduced in the presence of the TP53-inhibitor Pifitrin-α. Our data pave the way to further investigations on TP53 functionality as a marker predictive of response to miR-221 silencing, which might be relevant for clinical applications.

Metastasis accounts for the major cause of colorectal cancer (CRC) related mortality due to the lack of effective treatments. In this study, we integrated the single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data and identified the transcriptional coactivator SUB1 homolog (Sac-Saccharomyces cerevisiae)/PC4 (positive cofactor 4) associated with CRC metastasis. Elevated SUB1 expression was correlated with advanced tumor stage and poor survival in CRC. In vivo and vitro assays showed that SUB1 depletion could inhibit the invasive and metastatic abilities of CRC cells. SUB1 activated NF-κB signaling and its transcriptional target genes CXCL1 and CXCL3 to drive CRC metastasis. Mechanistically, SUB1 integrated with the E3 ubiquitin-protein ligase UBR5 and increased its protein level in CRC cells. Subsequently, the increased UBR5 mainly mediated Lys11-linked polyubiquitination and degradation of NF-κB negative regulator UBXN1, thus to activate the NF-κB signaling. Overall, our study demonstrated that SUB1 promoted CRC progression by modulating UBR5/UBXN1 and activating NF-κB signaling, providing a new therapeutic strategy for treating metastatic CRC through targeting SUB1.

Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.

Digestive tract tumors are heterogeneous and involve the dysregulation of multiple signaling pathways. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway plays a notable role in the oncogenesis of digestive tract tumors. Typically activated by pro-inflammatory cytokines, it regulates important biological processes, such as cell growth, differentiation, apoptosis, immune responses, and inflammation. The aberrant activation of this pathway manifests in different forms, including mutations in JAKs, overexpression of cytokine receptors, and sustained STAT activation, and contributes to promoting the malignant characteristics of cancer cells, including uncontrolled proliferation, resistance to apoptosis, enhanced invasion and metastasis, angiogenesis, acquisition of stem-like properties, and drug resistance. Numerous studies have shown that aberrant activation of the JAK-STAT pathway is closely related to the development and progression of digestive tract tumors, contributing to tumor survival, angiogenesis, changes in the tumor microenvironment, and even immune escape processes. In addition, this signaling pathway also affects the sensitivity of digestive tract tumors to chemotherapy and targeted therapy. Therefore, it is crucial to comprehensively understand the oncogenic mechanisms underlying the JAK-STAT pathway in order to develop effective therapeutic strategies against digestive tract tumors. Currently, several JAK-STAT inhibitors are undergoing clinical and preclinical trials as potential treatments for various human diseases. However, further investigation is required to determine the role of this pathway, as well as the effectiveness and safety of its inhibitors, especially in the context of digestive tract tumors. In this review, we provide an overview of the structure, classic activation, and negative regulation of the JAK-STAT pathway. Furthermore, we discuss the pathogenic mechanisms of JAK-STAT signaling in different digestive tract tumors, with the aim of identifying potential novel therapeutic targets. Video Abstract.

In recent decades, colorectal cancer (CRC) has turned into one of the most widespread malignancies, and the incidence of this malignancy is expected to increase. Despite considerable improvements in therapeutic approaches, the prognosis, and the management of CRC face many problems. Likely, the main limitation in the successful treatment of CRC is the lack of appropriate clinical therapeutic targets. As an effective target, the signal transducer and activator of transcription 3 (STAT3) are regulated by a wide range of genes and involved in cellular processes, including cell growth, migration, invasion, immunosuppression, and angiogenesis. Aberrant regulation of STAT3 signaling leads to cellular dysfunction, diseases, and malignancies, including CRC. Consequently, targeting this signaling pathway is considered one of the therapeutic strategies used in CRC treatment. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA molecules with partial or no protein-coding activity that participate in gene regulation at epigenetic, transcriptional, and post-transcriptional levels and regulate multiple signaling pathways, including STAT3 signaling (especially JAK/STAT). Therefore, these regulatory molecules are suggested to be very promising targets to present new insights into overcoming the limitations of conventional therapeutic strategies. Therefore, the current review study aimed to summarize the therapeutic and diagnostic significance of miRNAs and lncRNAs and their therapeutic and diagnostic significance related to the expression and activity of STAT3 in CRC.

To date, colorectal cancer (CRC) still has limited therapeutic efficacy and poor prognosis and there is an urgent need for novel targets to improve the outcome of CRC patients. The highly conserved ubiquitination modification mediated by E3 ubiquitin ligases is an important mechanism to regulate the expression and function of tumor promoters or suppressors in CRC. In this review, we provide an overview of E3 ligases in modulating various biological processes in CRC, including proliferation, migration, stemness, metabolism, cell death, differentiation and immune response of CRC cells, emphasizing the pluripotency of E3 ubiquitin ligases. We further focus on the role of E3 ligases in regulating vital cellular signal pathways in CRC, such as Wnt/β-catenin pathway and NF-κB pathway. Additionally, considering the potential of E3 ligases as novel targets in the treatment of CRC, we discuss what aspects of E3 ligases can be utilized and exploited for efficient therapeutic strategies.

Despite the clinical benefits of androgen deprivation therapy, most patients with advanced androgen-dependent prostate cancer (ADPC) eventually relapse and progress to lethal androgen-independent prostate cancer (AIPC), also termed castration-resistant prostate cancer (CRPC). MiRNAs can be packaged into exosomes (Exos) and shuttled between cells. However, the roles and mechanisms of exosomal miRNAs involved in CRPC progression have not yet been fully elucidated. Here, we find that miR-222-3p is elevated in AIPC cells, which results in remarkable enhancement of cell proliferation, migration, and invasion ability. Furthermore, Exos released by AIPC cells can be uptaken by ADPC cells, thus acclimating ADPC cells to progressing to more aggressive cell types in vitro and in vivo through exosomal transfer of miR-222-3p. Mechanistically, Exos-miR-222-3p promoted ADPC cells transformed to AIPC-like cells, at least in part, by activating mTOR signaling through targeting MIDN. Our results show that AIPC cells secrete Exos containing miRNA cargo. These cargos can be transferred to ADPC cells through paracrine mechanisms that have a strong impact on cellular functional remodeling. The current work underscores the great therapeutic potential of targeting Exo miRNAs, either as a single agent or combined with androgen receptor pathway inhibitors for CRPC treatment.

Gastrointestinal (GI) tumors (cancers of the esophagus, gastric, liver, pancreas, colon, and rectum) contribute to a large number of deaths worldwide. STAT3 is an oncogenic transcription factor that promotes the transcription of genes associated with proliferation, antiapoptosis, survival, and metastasis. STAT3 is overactivated in many human malignancies including GI tumors which accelerates tumor progression, metastasis, and drug resistance. Research in recent years demonstrated that noncoding RNAs (ncRNAs) play a major role in the regulation of many signaling pathways including the STAT3 pathway. The major types of endogenous ncRNAs that are being extensively studied in oncology are microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs can either be tumor-promoters or tumor-suppressors and each one of them imparts their activity via different mechanisms. The STAT3 pathway is also tightly modulated by ncRNAs. In this article, we have elaborated on the tumor-promoting role of STAT3 signaling in GI tumors. Subsequently, we have comprehensively discussed the oncogenic as well as tumor suppressor functions and mechanism of action of ncRNAs that are known to modulate STAT3 signaling in GI cancers.

Spermidine (SPD) is a natural polyamine that shows beneficial effects on osteoarthritis (OA). However, the effect of SPD on cartilage inflammation remains unknown. This study aimed to investigate the potential mechanisms underlying the protective effect of SPD against OA-induced articular cartilage degradation.

SW1353 human chondrocytes were treated with hydrogen peroxide and lipopolysaccharide to induce models of inflammation and oxidative stress, followed by different dose of SPD intervention. Moreover, mice that underwent anterior cruciate ligament transection were bred and treated with SPD. The effects of SPD were observed using a CCK-8 kit, real-time polymerase chain reaction, immunoblotting, and immunofluorescent assays.

SPD significantly increased the expression of antioxidant proteins, chondrogenic genes, and inflammatory factors both in vivo and in vitro. And injury of the mouse cartilage was also reduced by SPD. Moreover, SPD activated the Nrf2/KEAP1 pathway and inhibited STAT3 phosphorylation. BRG1 expression was decreased in osteoarthritic mouse cartilage, whereas SPD treatment caused an upregulation. However, when BRG1 was specifically inhibited by an adeno-associated virus and small interfering RNA, the antioxidant and anti-inflammatory effects of SPD were significantly diminished both in vitro and in vivo.

We found that SPD ameliorated cartilage damage in OA by activating the BRG1-mediated Nrf2/KEAP1 pathway. SPD and BRG1 may provide new therapeutic options or targets for the treatment of OA.

Protein interactions with the microRNA (miRNA)-mediated gene silencing protein Argonaute 2 (AGO2) control miRNA expression. miRNA biogenesis starts with the production of precursor transcripts and culminates with the loading of mature miRNA onto AGO2 by DICER1. Here we reveal an additional component to the regulatory mechanism for miRNA biogenesis involving the adaptor protein, growth factor receptor-bound protein 2 (GRB2). The N-terminal SH3 domain of GRB2 is recruited to the PAZ domain of AGO2 forming a ternary complex containing GRB2, AGO2 and DICER1. Using small-RNA sequencing we identified two groups of miRNAs which are regulated by the binding of GRB2. First, mature and precursor transcripts of mir-17~92 and mir-221 miRNAs are enhanced. Second, mature, but not precursor, let-7 family miRNAs are diminished suggesting that GRB2 directly affects loading of these miRNAs. Notably, the resulting loss of let-7 augments expression of oncogenic targets such as RAS. Thus, a new role for GRB2 is established with implications for cancer pathogenesis through regulation of miRNA biogenesis and oncogene expression.

Combined treatments employing lower concentrations of different drugs are used and studied to develop new and more effective anticancer therapeutic approaches. The combination therapy could be of great interest in the controlling of cancer. Regarding this, our research group has recently shown that peptide nucleic acids (PNAs) that target miR-221 are very effective and functional in inducing apoptosis of many tumor cells, including glioblastoma and colon cancer cells. Moreover, in a recent paper, we described a series of new palladium allyl complexes showing a strong antiproliferative activity on different tumor cell lines. The present study was aimed to analyze and validate the biological effects of the most active compounds tested, in combination with antagomiRNA molecules targeting two miRNAs, miR-221-3p and miR-222-3p. The obtained results show that a "combination therapy", produced by combining the antagomiRNAs targeting miR-221-3p, miR-222-3p and the palladium allyl complex 4d, is very effective in inducing apoptosis, supporting the concept that the combination treatment of cancer cells with antagomiRNAs targeting a specific upregulated oncomiRNAs (in this study miR-221-3p and miR-222-3p) and metal-based compounds represents a promising therapeutic strategy to increase the efficacy of the antitumor protocol, reducing side effects at the same time.

Chronic inflammation promotes the tumorigenesis and cell stemness maintenance of colorectal cancer (CRC). However, the bridge role of long noncoding RNA (lncRNA) in linking chronic inflammation to CRC development and progression needs better understanding. Here, we elucidated a novel function of lncRNA GMDS-AS1 in persistently activated signal transducer and transcription activator 3 (STAT3) and Wnt signaling and CRC tumorigenesis. Interleukin-6 (IL-6) and Wnt3a induced lncRNA GMDS-AS1 expression, which was highly expressed in the CRC tissues and plasma of CRC patients. GMDS-AS1 knockdown impaired the survival, proliferation and stem cell-like phenotype acquisition of CRC cells in vitro and in vivo. We performed RNA sequencing (RNA-seq) and mass spectrometry (MS) to probe target proteins and identify their contributions to the downstream signaling pathways of GMDS-AS1. In CRC cells, GMDS-AS1 physically interacted with the RNA-stabilizing protein HuR, thereby protecting the HuR protein from polyubiquitination- and proteasome-dependent degradation. HuR stabilized STAT3 mRNA and upregulated the levels of basal and phosphorylated STAT3 protein, persistently activating STAT3 signaling. Our research revealed that the lncRNA GMDS-AS1 and its direct target HuR constitutively activate STAT3/Wnt signaling and promote CRC tumorigenesis, the GMDS-AS1-HuR-STAT3/Wnt axis is a therapeutic, diagnostic and prognostic target in CRC.

Cancer immunity is regulated by several mechanisms that include co-stimulatory and/or co-inhibitory molecules known as immune checkpoints expressed by the immune cells. In colorectal cancer (CRC), CTLA-4, LAG3, TIM-3 and PD-1 are the major co-inhibitory checkpoints involved in tumor development and progression. On the other hand, the deregulation of transcription factors and cancer stem cells activity plays a major role in the development of drug resistance and in the spread of metastatic disease in CRC. In this review, we describe how the modulation of such transcription factors affects the response of CRC to therapies. We also focus on the role of cancer stem cells in tumor metastasis and chemoresistance and discuss both preclinical and clinical approaches for targeting stem cells to prevent their tumorigenic effect. Finally, we provide an update on the clinical applications of immune checkpoint inhibitors in CRC and discuss the regulatory effects of transcription factors on the expression of the immune inhibitory checkpoints with specific focus on the PD-1 and PD-L1 molecules.

The tumor microenvironment (TME) comprises a variety of immune cells, among which T cells exert a prominent axial role in tumor development or anti-tumor responses in patients with breast cancer (BC). High or low levels of anti-inflammatory cytokines, such as transforming growth factor β, in the absence or presence of proinflammatory cytokines, such as interleukin-6 (IL-6), delineate the fate of T cells toward either regulatory T (Treg) or T helper 17 (Th17) cells, respectively. The transitional state of RORγt⁺Foxp3⁺ Treg (IL-17-producing Treg) resides in the middle of this reciprocal polarization, which is known as Treg/IL-17-producing Treg/Th17 cell axis. TME secretome, including microRNAs, cytokines, and extracellular vesicles, can significantly affect this axis. Furthermore, immune checkpoint inhibitors may be used to reconstruct immune cells; however, some of these novel therapies may favor tumor development. Therefore, understanding secretory and cell-associated factors involved in their differentiation or polarization and functions may be targeted for BC management. This review discusses microRNAs, cytokines, and extracellular vesicles (as secretome), as well as transcription factors and immune checkpoints (as cell-associated factors), which influence the Treg/IL-17-producing Treg/Th17 cell axis in BC. Furthermore, approved or ongoing clinical trials related to the modulation of this axis in the TME of BC are described to broaden new horizons of promising therapeutic approaches.

The development of techniques and immunotherapies are widely applied in cancer treatment such as checkpoint inhibitors, adoptive cell therapy, and cancer vaccines apart from radiation therapy, surgery, and chemotherapy give enduring anti-tumor effects. Minority people utilize single-agent immunotherapy, and most people adopt multiple-agent immunotherapy. The difficulties are resolved by including the biomarkers to choose the non-responders' and responders' potentials. The possibility of the potential complications and side effects are examined to improve cancer therapy effects. The Head and Neck Squamous Cell Carcinoma (HNSCC) is analyzed with the help of programmed cell death ligand 1 (PD-L1) and Insulin-like growth factor (IGF). But how IGF and PD-L1 upregulation depends on IL-6, EGFR, and LIN28/Let7-related mechanisms are poorly understood. Briefly, IL-6 stimulates gene expressions of IGF-1/2, and IL-6 cross-activates IGF-1R signaling, NF-κB, and STAT3. NF-κB, up-regulating PD-L1 expressions. IL-6/JAK1 primes PD-L1 for STT3-mediated PD-L1 glycosylation, stabilizes PD-L1 and trafficks it to the cell surface. Moreover, ΔNp63 is predominantly overexpressed over TAp63 in HNSCC, elevates circulating IGF-1 levels by repressing IGFBP3, and activates insulin receptor substrate 1 (IRS1).TP63 and SOX2 form a complex with CCAT1 to promote EGFR expression. EGFR activation through EGF binding extends STAT3 activation, and EGFR and its downstream signaling prolong PD-L1 mRNA half-life. PLC-γ1 binding to a cytoplasmic motif of elevated PD-L1 improves EGF-induced activation of inositol 1,4,5-tri-phosphate (IP3), and diacylglycerol (DAG) subsequently elevates RAC1-GTP. RAC1-GTP was convincingly demonstrated to induce the autocrine production and action of IL-6/IL-6R, forming a feedback loop for IGF and PD-L1 upregulation. Furthermore, the LIN28-Let7 axis mediates the NF-κB-IL-6-STAT3 amplification loop, activated LIN28-Let7 axis up-regulates RAS, AKT, IL-6, IGF-1/2, IGF-1R, Myc, and PD-L1, plays pivotal roles in IGF-1R activation and Myc, NF-κB, STAT3 concomitant activation. Therefore, based on a detailed mechanisms review, our article firstly reveals that IL-6, EGFR, and LIN28/Let7-related mechanisms mediate PD-L1 and IGF upregulation in HNSCC, which comprehensively influences immunity, inflammation, metabolism, and metastasis in the tumor microenvironment, and might be fundamental for overcoming therapy resistance.

Oxidative stress is an important pathogenic factor in ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC), further impairing the entire colon. Intestinal epithelial cells (IECs) are crucial components of innate immunity and play an important role in maintaining intestinal barrier function. Recent studies have indicated that microRNA-222-3p (miR-222-3p) is increased in colon of UC and colorectal cancer (CRC) patients, and miR-222-3p is a crucial regulator of oxidative stress. However, whether miR-222-3p influences IEC oxidative stress in UC and CAC remains unknown. This study investigated the effect of miR-222-3p on the regulation of IEC oxidative stress in UC and CAC. An in vitro inflammation model was established in NCM460 colonic cells, mouse UC and CAC models were established in vivo, and IECs were isolated. The biological role and mechanism of miR-222-3p-mediated oxidative stress in UC and CAC were determined. We demonstrated that miR-222-3p expression was notably increased in dextran sulfate sodium (DSS)-induced NCM460 cells and IECs from UC and CAC mice. In vitro, these results showed that the downregulation of miR-222-3p reduced oxidative stress, caspase-3 activity, IL-1β and TNF-α in DSS-induced NCM460 cells. We further identified BRG1 as the target gene of miR-222-3p, and downregulating miR-222-3p alleviated DSS-induced oxidative injury via promoting BRG1-mediated activation Nrf2/HO-1 signaling in NCM460 cells. The in vivo results demonstrated that inhibiting miR-222-3p in IECs significantly relieved oxidative stress and inflammation in the damaged colons of UC and CAC mice, as evidenced by decreases in ROS, MDA, IL-1β and TNF-α levels and increases in GSH-Px levels. Our study further demonstrated that inhibiting miR-222-3p in IECs attenuated oxidative damage by targeting BRG1 to activate the Nrf2/HO-1 signaling. In summary, inhibiting miR-222-3p in IECs attenuates oxidative stress by targeting BRG1 to activate the Nrf2/HO-1 signaling, thereby reducing colonic inflammation and tumorigenesis.

High levels of the inflammatory cytokine IL-6 in the bone marrow are associated with poor outcomes in pediatric acute myeloid leukemia (pAML), but its etiology remains unknown. Using RNA-seq data from pre-treatment bone marrows of 1489 children with pAML, we show that > 20% of patients have concurrent IL-6, IL-1, IFNα/β, and TNFα signaling activity and poorer outcomes. Targeted sequencing of pre-treatment bone marrow samples from affected patients (n = 181) revealed 5 highly recurrent patterns of somatic mutation. Using differential expression analyses of the most common genomic subtypes (~60% of total), we identify high expression of multiple potential drivers of inflammation-related treatment resistance. Regardless of genomic subtype, we show that JAK1/2 inhibition reduces receptor-mediated inflammatory signaling by leukemic cells in-vitro. The large number of high-risk pAML genomic subtypes presents an obstacle to the development of mutation-specific therapies. Our findings suggest that therapies targeting inflammatory signaling may be effective across multiple genomic subtypes of pAML.

Thousands of unique noncoding RNAs (ncRNAs) exist within the genomes of higher eukaryotes. Upon virus infection, the host generates interferons (IFNs), which initiate the expression of hundreds of interferon-stimulated genes (ISGs) through IFN receptors on the cell surface, establishing a barrier as the host's antiviral innate immunity. With the development of novel RNA-sequencing technology, many IFN-induced ncRNAs have been identified, and increasing attention has been given to their functions as regulators involved in the antiviral innate immune response. IFN-induced ncRNAs regulate the expression of viral proteins, IFNs, and ISGs, as well as host genes that are critical for viral replication, cytokine and chemokine production, and signaling pathway activation. This review summarizes the complex regulatory role of IFN-induced ncRNAs in antiviral innate immunity from the above aspects, aiming to improve understanding of ncRNAs and provide reference for the basic research of antiviral innate immunity.

Breast cancers (BrCas) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2+ BrCa to HER2-targeting drugs. CDK8 was in the top 1% of all genes ranked by correlation with shorter relapse-free survival among treated HER2+ BrCa patients. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2+ BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. The synergistic effects were mediated in part through the PI3K/AKT/mTOR pathway and reduced by PI3K inhibition. Combination of HER2- and CDK8/19-targeting agents inhibited STAT1 and STAT3 phosphorylation at S727 and up-regulated tumor suppressor BTG2. The growth of xenograft tumors formed by lapatinib-sensitive or -resistant HER2+ breast cancer cells was partially inhibited by SNX631 alone and strongly suppressed by the combination of SNX631 and lapatinib, overcoming lapatinib resistance. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2+ BrCa.

Inflammatory bowel disease (IBD), classified primarily between Crohn's disease and ulcerative colitis, is a collection of chronic gastrointestinal inflammatory conditions that cause multiple complications because of systemic alterations in the immune response. One major player is microRNA (miRNA), which is found to be associated with multiple pathways in mediating inflammation, especially those of a chronic nature in IBD, as well as irritable bowel syndrome. Although there have been studies linking miRNA alterations in IBD, even differentiating Crohn's disease and ulcerative colitis, this review focuses mainly on how miRNAs cause and mechanistically influence the pathologic complications of IBD. In addition to its role in the well-known progression towards colorectal cancer, we also emphasize how miRNA manifests the many extraintestinal complications in IBD such as cardiovascular diseases; neuropsychiatric conditions such as depression and anxiety disorders; and others, including various musculoskeletal, dermatologic, ocular, and hepatobiliary complications. We conclude through a description of its potential use in bettering diagnostics and the future treatment of IBD and its systemic symptoms.

Tuberculosis (TB), the world's deadliest bacterial infection, afflicts more human males than females, with a male/female (M/F) ratio of 1.7. Sex disparities in TB prevalence, pathophysiology, and clinical manifestations are widely reported, but the underlying biological mechanisms remain largely undefined. This review assesses epidemiological data on sex disparity in TB, as well as possible underlying hormonal and genetic mechanisms that might differentially modulate innate and adaptive immune responses in males and females, leading to sex differences in disease susceptibility. We consider whether this sex disparity can be extended to the efficacy of vaccines and discuss novel animal models which may offer mechanistic insights. A better understanding of the biological factors underpinning sex-related immune responses in TB may enable sex-specific personalized therapies for TB.

Overexpression of M3 subtype muscarinic receptors (M3R) hastens colon cancer progression. As microRNA (miRNA) expression is commonly dysregulated in cancer, we used microarrays to examine miRNA profiles in muscarinic receptor agonist-treated human colon cancer cells. We used quantitative RT-PCR (qPCR) to validate microarray results and examine miRNA expression in colon cancers and adjacent normal colon. These assays revealed that acetylcholine (ACh) treatment robustly induced miR-222 expression; miR-222 levels were three-fold higher in cancer compared to normal colon. In kinetic studies, ACh induced a 4.6-fold increase in pri-miR-222 levels within 1 h, while mature miR-222 increased gradually to 1.8-fold within 4 h. To identify post-M3R signaling mediating these actions, we used chemical inhibitors and agonists. ACh-induced increases in pri-miR-222 were attenuated by pre-incubating cells with atropine and inhibitors of protein kinase C (PKC) and p38 MAPK. Treatment with a PKC agonist, phorbol 12-myristate 13-acetate, increased pri-miR-222 levels, an effect blocked by PKC and p38 MAPK inhibitors, but not by atropine. Notably, treatment with ACh or transfection with miR-222 mimics increased cell proliferation; atropine blocked the effects of ACh but not miR-222. These findings identify a novel mechanism whereby post-M3R PKC/p38 MAPK signaling stimulates miR-222 expression and colon cancer cell proliferation.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.