Recent Progress on Nanomedicine-Mediated Repolarization of Tumor-Associated Macrophages for Cancer Immunotherapy.

Tumor-associated macrophages (TAMs) constitute the largest number of immune cells in the tumor microenvironment (TME). They play an essential role in promoting tumor progression and metastasis, which makes them a potential therapeutic target for cancer treatment. TAMs are usually divided into two categories: pro-tumoral M2-like TAMs and antitumoral M1 phenotypes at either extreme. The reprogramming of M2-like TAMs toward a tumoricidal M1 phenotype is of particular interest for the restoration of antitumor immunity in cancer immunotherapy. Notably, nanomedicines have shown great potential for cancer therapy due to their unique structures and properties. This review will briefly describe the biological features and roles of TAMs in tumor, and then discuss recent advances in nanomedicine-mediated repolarization of TAMs for cancer immunotherapy. Finally, perspectives on nanomedicine-mediated repolarization of TAMs for effective cancer immunotherapy are also presented.

Bioengineered Extracellular Vesicles Delivering siMDM2 Sensitize Oxaliplatin Therapy Efficacy in Colorectal Cancer.

Oxaliplatin (OXA) is the first-line drug for the treatment of colorectal cancer (CRC), and susceptibility to drug resistance affects patient prognosis. However, the exact underlying mechanisms remain unclear. Platinum-acquired resistance in CRC is a continuous transition process; though, current research has mainly focused on the end state of drug resistance, and the early events of drug resistance have been ignored. In this study, single-cell transcriptome sequencing is combined with a dynamic network biomarker (DNB), and found that the functional inhibition of the mitochondrial electron transport chain complex I occur early in the development of attained resistance to OXA in CRC cells, as evidenced by a decrease in the levels of subunit proteins, primarily NDUFB8. Specifically, the mouse double minute 2 homologue (MDM2) mediates the ubiquitination and degradation of NDUFB8, reducing intracellular reactive oxygen species (ROS) generation under chemotherapeutic stress, consequently contributing to drug resistance. Based on this, the study constructs engineered extracellular vesicles carrying siMDM2 by electroporation and validates the application of EV-siMDM2 to improve the efficacy of OXA-based chemotherapy by inhibiting the MDM2/NDUFB8/ROS signaling axis in patient-derived xenograft (PDX) and hepatic and pulmonary metastasis mouse models, thus providing new ideas and an experimental basis for the platinum-resistant treatment of CRC.

Risk factors for postoperative complications in patients undergoing cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: A meta-analysis and systematic review.

OBJECTIVE: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is one of the most effective treatments for intraperitoneal malignancies. However, current research on risk factors for postoperative complications needs to be more consistent. This study aimed to conduct a meta-analysis of the risk factors for postoperative complications in CRS + HIPEC patients. METHODS: Studies meeting the inclusion criteria were screened by searching the Embase, PubMed, Cochrane and Web of Science databases. RevMan and STATA software were used to analyze the data extracted from the included articles. RESULTS: A total of 15 articles with 4021 patients were included in the meta-analysis. The results revealed that sex, elevated peritoneal cancer index, prolonged duration of surgery and smoking habits were risk factors for postoperative complications in CRS + HIPEC patients. In contrast, BMI, eGFR, age, history of preoperative chemotherapy, history of preoperative surgery, and history of neoadjuvant therapy had no significant effect on postoperative complications in the CRS + HIPEC group. The effects of diabetes, hypertension, preoperative albumin level, tumor location and chemotherapy regimen on the occurrence of complications need to be further investigated. CONCLUSIONS: We identified several risk factors for postoperative complications after CRS + HIPEC, which should help clinicians minimize the incidence of postoperative complications and make more beneficial decisions for cancer patients who need treatment.

Shellac-based delivery systems for food bioactive compounds.

Shellac is a natural resin featuring some attractive properties such as amphiphilicity, pH responsiveness, biocompatibility, and biodegradability. There has been increasing interest in employing shellac for controlled delivery of food bioactive compounds. This review outlines the recent advances in different types of shellac-based delivery systems, including nanoparticles, zein-shellac particles, hydrogels, nanofibers, and nanomicelles. The preparation method, formation mechanism, structure, and delivery performance are investigated. These systems could improve the stability and shelf-life of bioactive compounds, allow for targeted release at the small intestine or colon site, and increase bioavailability. The deficiencies and challenges of each of the systems are also discussed. The promising results in this review could guide future trends in more efficient shellac-based delivery platforms for functional food applications.

Survival prognostic in different age groups of patients undergoing local versus radical excision for rectal cancer: a study based on the SEER database.

Age significantly affects the prognosis of patients with rectal cancer after radical excision (RE), and local excision (LE) is an alternative surgical procedure to RE. To compare the survival prognosis in different age groups of LE versus RE for rectal cancer. Patients diagnosed with rectal adenocarcinoma treated by LE or RE from 2010 to 2017 were obtained from the SEER database. The primary outcomes are 5-year OS and CSS. A total of 11,170 patients were eventually included, and there were 490 patients in LE and RE groups, respectively, after 1:1 propensity score matching. The 5-year OS and CSS after LE were significantly better in < 50 years and 50-66 years groups than in > 66 years group (5-year OS: 95.70% vs 88.40% vs 67.00%, P < 0.001; 5-year CSS: 95.70% vs 96.30% vs 82.60%, P < 0.001). No statistical significance was found for the differences in 5-year OS and CSS between LE and RE in < 50, 50-66, and > 66 years group (P > 0.05). Multivariate analysis showed age > 66 years, poorly differentiated or undifferentiated (Grade III/IV), and tumor size 3 to 5 cm was independent risk factors for 5-year OS after LE; age > 66 years, perineural invasion, and tumor size 3 to 5 cm were the 5-year CSS independent risk factors for after LE. We found that the survival prognosis of younger rectal cancer patients treated with LE was significantly better than older (> 66 years) patients, and the survival prognosis of rectal cancer patients in the three age groups was similar between LE and RE.

Comprehensive analysis of a novel subtype of immune microenvironment-derived HPV-infected colorectal cancer.

BACKGROUND: The current study proposed a novel subtype, Human papillomavirus (HPV)-infected colorectal cancer (CRC), to understand the impact of HPV on CRC. METHODS: We assessed the prevalence and clinical implications of HPV in CRC by integrating a single cohort in Guangdong Provincial People's Hospital and public datasets. Differential gene, pathway enrichment, and immune infiltration analysis were conducted to explore the patterns in HPV-infected CRC. Quantitative polymerase chain reaction, cell proliferation, scratch, and flow cytometry assays were employed to validate the impact of HPV on CRC. RESULTS: The study revealed a high prevalence of HPV infection in CRC, with infection rates ranging from 10% to 31%. There was also a significant increase in tumor proliferation in HPV-infected CRC. The study showed increased immune cell infiltration, including T cells, γδ T cells, cytotoxic cells, and plasmacytoid dendritic cells in HPV-infected CRC (P < 0.05). Furthermore, our findings confirmed that HPV infection promoted M1 polarization. Our results demonstrated that low ISM2 expression was associated with a less advanced clinical stage (P < 0.001) and better survival outcomes (P = 0.039). Low ISM2 expression correlated with a strong tumor immune response, potentially contributing to the improved survival observed in HPV-infected CRC. CONCLUSIONS: These findings provided a novel subtype of HPV-infected CRC. The subtype with a better prognosis showed a "hot" tumor immune microenvironment that may be responsive to immunotherapy.

Prognostic impact of tumor budding in rectal cancer after neoadjuvant therapy: a systematic review and meta-analysis.

BACKGROUND: Tumor budding (TB) is a negative prognostic factor in colorectal cancer; however, its prognostic impact following neoadjuvant therapy for patients with rectal cancer remains unclear. This study aims to assess the prognostic impact of TB and the correlation between TB and other pathological features in patients with rectal cancer after neoadjuvant therapy. METHODS: A comprehensive search of PubMed, Embase, Cochrane, Scopus, CNKI, Wanfang, and ClinicalKey databases was conducted for studies on the prognosis of TB in rectal cancer after neoadjuvant therapy from the inception of the databases to January 2023, and the final literature included was determined using predefined criteria. Quality assessment of the studies included, extraction of general and prognostic information from them, and meta-analyses were carried out progressively. RESULTS: A total of 11 studies were included, and the results of the meta-analysis showed that high-grade tumor budding (TB-1) increased the risk of poor 5-year disease-free survival (HR = 1.75, 95% CI 1.38-2.22, P < 0.00001), 5-year overall survival (HR = 1.77, 95% CI 1.21-2.59, P = 0.003), local recurrence (OR = 4.15, 95% CI 1.47-11.75, P = 0.007), and distant metastasis (OR = 5.36, 95% CI 2.51-11.44, P < 0.0001) in patients with rectal cancer after neoadjuvant therapy. TB-1 was significantly associated with poor differentiation and lymphatic, perineural, and venous invasion. CONCLUSION: Tumor budding is significantly correlated with unfavorable prognosis and poor pathological characteristics following neoadjuvant therapy for rectal cancer. We anticipate more high-quality, prospective studies in the future to confirm our findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022377564.

SIK1 suppresses colorectal cancer metastasis and chemoresistance via the TGF-ß signaling pathway.

In the present study, we investigated the role of salt-induced kinase 1 (SIK1), a serine/threonine kinase protein, in colorectal cancer (CRC). Despite the reported association of SIK1 with tumor malignancy suppression in various cancers, limited research has been conducted on its function in CRC. Our findings revealed that SIK1 expression was low in CRC cells. The results of a KEGG pathway analysis showed a strong association between SIK1 and the TGF-ß signaling pathway. In addition, a coimmunoprecipitation assay validated the interaction between SIK1 and Smad7. Our data indicate that SIK1 inhibited the phosphorylation of Smad2, a critical molecule in the Smad-related TGF-ß pathway, and downstream target genes of the TGF-ß pathway. Furthermore, SIK1 was found to inhibit indicators of epithelial-mesenchymal transition (EMT) and reverse oxaliplatin resistance in CRC. Additionally, SIK1 reduced cell migration and invasion. Our results suggest that the inhibitory effect of SIK1 on the TGF-ß pathway contributes to the suppression of metastasis and oxaliplatin chemoresistance in CRC. However, this effect was reversed by galunisertib (LY2157299). In conclusion, our findings provide novel insights into the role of SIK1 in the regulation of the TGF-ß pathway in CRC, suggesting its potential as a therapeutic target for the treatment of CRC. Further studies are required to fully characterize the mechanism underlying these observations and to validate these findings in animal models.

Single-cell and spatial transcriptome analysis reveals the cellular heterogeneity of liver metastatic colorectal cancer.

In this study, we comprehensively charted the cellular landscape of colorectal cancer (CRC) and well-matched liver metastatic CRC using single-cell and spatial transcriptome RNA sequencing. We generated 41,892 CD45- nonimmune cells and 196,473 CD45+ immune cells from 27 samples of six CRC patients, and found that CD8_CXCL13 and CD4_CXCL13 subsets increased significantly in liver metastatic samples that exhibited high proliferation ability and tumor-activating characterization, contributing to better prognosis of patients. Distinct fibroblast profiles were observed in primary and liver metastatic tumors. F3+ fibroblasts enriched in primary tumors contributed to worse overall survival by expressing protumor factors. However, MCAM+ fibroblasts enriched in liver metastatic tumors might promote generation of CD8_CXCL13 cells through Notch signaling. In summary, we extensively analyzed the transcriptional differences of cell atlas between primary and liver metastatic tumors of CRC by single-cell and spatial transcriptome RNA sequencing, providing different dimensions of the development of liver metastasis in CRC.

A novel nomogram based on cell cycle-related genes for predicting overall survival in early-onset colorectal cancer.

BACKGROUND: Although the incidence of late-onset colorectal cancer (LOCRC) has decreased, the incidence of early-onset colorectal cancer (EOCRC) is still rising dramatically. Heterogeneity in the genomic, biological, and clinicopathological characteristics between EOCRC and LOCRC has been revealed. Therefore, the previous prognostic models based on the total CRC patient population might not be suitable for EOCRC patients. Here, we constructed a prognostic classifier to enhance the precision of individualized treatment and management of EOCRC patients. METHODS: EOCRC expression data were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The regulatory pathways were explored by gene set enrichment analysis (GSEA). The prognostic model was developed by univariate Cox-LASSO-multivariate Cox regression analyses of GEO samples. TCGA samples were used to verify the model. The expression and mutation profiles and immune landscape of the high-risk and low-risk cohorts were analyzed and compared. Finally, the expression and prognostic value of the model genes were verified by immunohistochemistry and qRT‒PCR analysis. RESULTS: The cell cycle was identified as the most significantly enriched oncological signature of EOCRC. Then, a 4-gene prognostic signature comprising MCM2, INHBA, CGREF1, and KLF9 was constructed. The risk score was an independent predictor of overall survival. The area under the curve values of the classifier for 1-, 3-, and 5-year survival were 0.856, 0.893, and 0.826, respectively, in the training set and 0.749, 0.858, and 0.865, respectively, in the validation set. Impaired DNA damage repair capability (p < 0.05) and frequent PIK3CA mutations (p < 0.05) were found in the high-risk cohort. CD8 T cells (p < 0.05), activated memory CD4 T cells (p < 0.01), and activated dendritic cells (p < 0.05) were clustered in the low-risk group. Finally, we verified the expression of MCM2, INHBA, CGREF1, and KLF9. Their prognostic value was closely related to age. CONCLUSION: In this study, a robust prognostic classifier for EOCRC was established and validated. The findings may provide a reference for individualized treatment and medical decision-making for patients with EOCRC.

Efficacy and safety of apatinib combined with radiotherapy in the treatment of advanced pancreatic cancer: a meta-analysis.

OBJECTIVE: At present, pancreatic cancer (PC) has a high morbidity and mortality rate and a poor prognosis. The aim of this article was to study the efficacy and safety of apatinib combined with radiotherapy in the treatment of advanced PC. METHODS: The PubMed, Cochrane Library, Embase, Wanfang, CNKI, VIP, and CBM databases were searched by computer to identify studies on the application of apatinib in patients with advanced PC. The patients in the included study were divided into an observation group (apatinib combined with radiotherapy) and a control group (radiotherapy only), and meta-analysis was performed for each outcome with Revman 5.4 software. This study was successfully registered on the PROSPERO website, and the registration number is CRD: 42,022,384,056 (available at https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384056 ). RESULTS: A total of 7 randomized controlled trials (RCTs) with 428 patients were included, including 215 in the observation group and 213 in the control group. Compared with the control group, the observation group showed a greater objective response rate [OR = 3.26, 95% CI (2.18, 4.87), P < 0.0001], disease control rate [OR = 5.04, 95% CI (3.12, 8.12), P < 0.0001], complete response rate [OR = 3.87, 95% CI (1.51, 9.88), P = 0.005], and partial response rate [OR = 2.43, 95% CI (1.63, 3.61), P < 0.001], The 1-year survival rate [OR = 2.39, 95% CI (1.15, 4.96), P < 0.05], 2-year survival rate [OR = 2.41, 95% CI (1.03, 5.61), P < 0.05], progression-free survival time [MD = 1.17, 95% CI (0.37, 1.96), P < 0.05], overall survival time [MD = 1.47, 95% CI (0.13, 2.80), P < 0.05], while the stability rate [OR = 1.14, 95% CI (0.72, 1.81), P = 0.58] and various complications were not significantly different between the two groups. CONCLUSION: Apatinib combined with radiotherapy was more effective than radiotherapy alone in the treatment of advanced pancreatic cancer (PC), and apatinib had acceptable safety. However, since our study was limited by the quantity and quality of the included studies, we look forward to more large-sample, multicentre, and high-quality RCTs in the future to verify the conclusions.

Development of a prognostic model based on ferroptosis-related genes for colorectal cancer patients and exploration of the biological functions of NOS2 in vivo and in vitro.

Background: Ferroptosis is involved in many malignant tumors and has been implicated in important mechanisms of colorectal cancer (CRC) suppression. However, the prognostic and predictive values of the ferroptosis activation pattern in CRC patients have not been noted. Here, we aimed to construct and validate a prediction model based on ferroptosis-related genes (FRGs) for CRC patients and investigated the expression pattern and biological function of the most significantly altered gene. Methods: A total of 112 FRGs were obtained from the FerrDb website, and the clinical characteristics of 545 CRC patients and their global gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Survival-related FRGs were identified by Cox proportional hazards regression analysis. Finally, the expression pattern and biological function of NOS2, the most implicated gene was explored in vitro and in vivo. Results: The prediction model was established based on 8 FRGs. Patients in the high- or low-risk group were stratified based on the median risk value calculated by our model, and patients in the high-risk group experienced poor overall survival (p<0.01). Further validation demonstrated that the FRG model acted as an independent prognostic indicator for CRC patients (HR=1.428, 95% CI, 1.341-1.627; p<0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for 5-year survival was 0.741. NOS2 was one of the most significantly affected FRGs and was highly expressed in malignant tissue, but it inhibited tumor growth and induced tumor cell death in vitro and in vivo, possibly by repressing the NF-κB pathway. Conclusion: Our study revealed that FRGs have potential prognostic value in CRC patients and that NOS2 suppresses tumor progression, providing a novel therapeutic target for CRC treatment based on ferroptosis.

Delivery of Engineered Primary Tumor-Derived Exosomes Effectively Suppressed the Colorectal Cancer Chemoresistance and Liver Metastasis.

Liver metastasis is one of the major causes of colorectal cancer (CRC)-related morbidity and mortality. Delivering small interfering RNAs (siRNAs) or noncoding RNAs has been reported as a promising method to target liver metastasis and chemoresistance in CRC. Here, we report a noncoding RNA delivery system using exosomes derived from primary patient cells. Coiled-coil domain-containing protein 80 (CCDC80) was strongly associated with CRC liver metastasis and chemoresistance, a finding validated by bioinformatic analysis and clinical specimens. Silencing CCDC80 significantly increased sensitivity to chemotherapy agents in OXA-resistant cell lines and a mouse model. The primary cell-derived exosome delivery system was designed to simultaneously deliver siRNAs targeting CCDC80 and increase chemotherapy sensitivity in the distant CRC liver metastasis mouse models and patient-derived xenograft mouse models. We further validated the antitumor effect in an ex vivo model of chemoresistant CRC organoids and a patient-derived organoid xenograft model. Tumor-bearing mice treated with the siRNA-delivering exosomes and hepatectomy showed ideal overall survival. Our results provide a therapeutic target and represent a possible therapeutic alternative for patients with CRC and distant metastasis and in cases of chemoresistance.

Stabilization of anthocyanins by simultaneous encapsulation-copigmentation via protein-polysaccharide polyelectrolyte complexes.

This study prepared a series of polyelectrolyte complexes (PECs) composed of heated whey protein isolate (HWPI) and different polysaccharides for simultaneous encapsulation and copigmentation of anthocyanins (ATC) and their ultimate stabilization. Four polysaccharides including chondroitin sulfate, dextran sulfate, gum arabic, and pectin were chosen due to their abilities to simultaneously complex with HWPI and copigment ATC. At pH 4.0, these PECs were formed with an average particle size of 120-360 nm, the ATC encapsulation efficiency of 62-80%, and the production yield of 47-68%, depending on the type of polysaccharides. The PECs effectively inhibited the degradation of ATC during storage and when exposed to neutral pH, ascorbic acid, and heat. Pectin had the best protection, followed by gum arabic, chondroitin sulfate, and dextran sulfate. The stabilizing effects were associated with the hydrogen bonding, hydrophobic and electrostatic interactions between HWPI and polysaccharides, conferring dense internal network and hydrophobic microenvironment in the complexes.

Outcomes after the watch-and-wait strategy and local excision treatment for rectal cancer: a meta-analysis.

BACKGROUND: The watch-and-wait (W&W) strategy and local excision (LE) have been used in patients with clinical complete response (cCR) for rectal cancer, but the comparative outcomes of the two strategies are controversial. We compared the efficacy of the W&W strategy with LE for rectal cancer patients after neoadjuvant chemoradiotherapy (nCRT) or total neoadjuvant therapy (TNT). RESEARCH DESIGN AND METHODS: Several domestic and foreign databases were searched for the relevant literature on comparative trials of the W&W strategy and LE surgery for rectal cancer after neoadjuvant therapy with the following outcomes; differences in local recurrence (LR), distant metastasis (DM/DM+LR), 3-year disease-free survival (DFS), 3-year local recurrence-free survival (LRFS) and 3-year overall survival (OS). RESULTS: Nine articles, were analyzed. Overall, 442 patients were included, with 267 and 175 patients in the W&W and LE groups, respectively. Meta-analysis results showed no significant differences the between W&W and LE groups with respect to LR, DM/DM+LR, 3-year DFS, 3-year LRFS, and 3-year OS. This study has been registered in PROSPERO (registration number: CRD42022331208). CONCLUSION: The W&W strategy may be preferred for some rectal cancer patients who select LE and reach cCR or near cCR after nCRT or TNT.

Prognostic value of final pathological stage in colon adenocarcinoma after neoadjuvant chemotherapy: A propensity score-matched study.

Background: Neoadjuvant chemotherapy (NAC) could improve local tumor control of locally advanced colon cancer (LACC), but the prognostic value of yp stage in colon cancer remains unknown. Here, we aimed to ascertain yp stage as an indicator for LACC prognosis after NAC. Methods: The data of patients diagnosed with colon adenocarcinoma between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results database. After 1:2 propensity score matching, cancer-specific survival (CSS) and overall survival (OS) were compared between the NAC and Non-NAC groups of different stage classifications. The correlation between clinical and pathological factors and CSS was identified. Results: A total of 49, 149, and 81 matched pairs of stage 0-I, II, and III patients, respectively, were generated for analysis. For stage 0-I (p = 0.011) and III (p = 0.015), only CSS in the NAC groups were inferior. Receiving NAC was an independent prognostic risk factor for patients with stage 0-I (hazard ratio, 7.70; 95% confidence interval, 1.820-32.5; p = 0.006) and stage III (hazard ratio, 1.73; 95% confidence interval, 1.11-2.68; p = 0.015). Conclusions: The CSS was poorer among LACC patients who underwent NAC than among those who did not. The yp stage of colon cancer after NAC has distinctive significance, which may contribute to predicting the prognosis and guiding the treatment of LACC patients after NAC.

Precision medicine-guided co-delivery of ASPN siRNA and oxaliplatin by nanoparticles to overcome chemoresistance of colorectal cancer.

The development of chemoresistance is a major hurdle for the treatment of colorectal cancer (CRC), which contributes remarkably to the poor clinical prognosis. Nanodrug delivery systems show great potential in overcoming chemoresistance, but limited by the lack of identification of chemoresistance targets from cancer patients. In the present study, we enrolled chemotherapy-resistant or sensitive CRC patients and used the next-generation RNA sequencing to reveal that Asporin (ASPN) is highly expressed in tumor tissues from oxaliplatin (OXA)-resistant patients and closely correlated with a poor prognosis of CRC. Downregulation of ASPN reversed OXA resistance and promoted cell apoptosis both in vitro and in vivo. To overcome ASPN-mediated OXA resistance, we constructed a nanoparticle-based co-delivery system (denoted as PPO-siASPN) for simultaneous delivery of OXA and siRNA targeting ASPN (siASPN). PPO-siASPN not only facilitated the intracellular delivery of OXA through the enhanced cellular uptake, but effectively suppressed ASPN expression for synergistic antitumor activity in vitro and in vivo. In the more clinically relevant patient-derived xenograft (PDX) mouse model, systemic administration of PPO-siASPN achieved a remarkable therapeutic effect. This study uncovered the critical role of ASPN in causing OXA resistance in CRC patients and suggests a promising nanoformulation that may be more effective than current standard-of-care medications.

Pan-Cancer Analysis Reveals SH3TC2 as an Oncogene for Colorectal Cancer and Promotes Tumorigenesis via the MAPK Pathway.

SH3 domain and tetrapeptide repeat 2 (SH3TC2) is a protein-encoding gene and has previously been described as a critical signaling hub for neurological disorders. Although increasing evidence supports a vital role of SH3TC2 in the tumorigenesis of various kinds of cancer, no systematic analysis of SH3TC2 is available. The function and mechanism of SH3TC2 in other cancers remain unknown. Thus, this study aimed to analyze SH3TC2 in various kinds of cancer to find its tumorigenic role in one or more specific cancers. In the current study, we analyzed the expression level and prognostic value of SH3TC2 in different tumors in the TCGA-GTEx pan-cancer dataset. Subsequently, the prognostic role and mechanism of SH3TC2 in colorectal cancer (CRC) were further explored via clinical samples and in vitro and in vivo experiments. We observed differential expression of SH3TC2 in colon adenocarcinoma (COAD), acute myeloid leukemia (LAML), READ (rectum adenocarcinoma), SKCM (skin cutaneous melanoma), and TGCT (testicular germ cell tumors). Subsequently, SH3TC2 showed a significant effect on the clinical stage and prognostic value in CRC, LAML, and SKCM. Moreover, we found in the TCGA database and seven GEO datasets that SH3TC2 was significantly highly expressed in tumor tissue. Through enrichment analysis of SH3TC2 and its co-expressed genes, we found that SH3TC2 may play a role in the MAPK signaling pathway. Correlation analysis indicated that SH3TC2 was significantly associated with multiple key factors in the MAPK signaling pathway. Additionally, higher expression of SH3TC2 was found in tumor tissue in our cohort including 40 CRC patients. Overexpression of SH3TC2 may imply poor prognosis. Knockdown of SH3TC2 significantly inhibited tumor invasion, migration, and proliferation. More importantly, knockdown of SH3TC2 inhibited tumor growth in a CRC mouse model. The study preliminarily conducted a pan-cancer study of SH3TC2 and further explored the mechanism of SH3TC2 in CRC. Our research revealed that higher expression of SH3TC2 may promote CRC progression and invasion via the MAPK signaling pathway.

Notch signaling mutations increase intra-tumor chemokine expression and predict response to immunotherapy in colorectal cancer.

BACKGROUND: The Notch signaling mutation is associated with enhanced anti-tumor immune response in colorectal cancer (CRC). In this study, we aim to investigate the underlying mechanism and the predictive potential of Notch signaling mutation for responding to immunotherapy in CRC. METHODS: We analyzed the immune response associated genes in CRC with Notch signaling mutation concomitant with or without microsatellite instability (MSI) using TCGA dataset and investigated the mutation profiles of the Notch signaling pathway using cBioPortal. The Notch signaling scores and immune cell infiltration scores in different groups were calculated. We applied the Kaplan-Meier method for survival analysis in CRC patients who underwent immunotherapy, and the log-rank test to determine the statistically significant differences in survival. Notch1-knock-down cell line was constructed to detect the pathway and gene variations. RESULTS: We found that Notch signaling pathway mutation was associated with activated immune response, especially in those with MSI. Such association is useful for predicting a prolonged overall survival of CRC patients who underwent immune checkpoint inhibitor treatment. The mutation resulted in the functional loss of Notch signaling and may modulate the tumor immune microenvironment by increasing the expression of chemokines that are important for recruiting immune cells. CONCLUSIONS: The Notch signaling mutation can modulate the chemotaxis of immune cells by upregulating the chemokine levels of the tumor immune microenvironment, and CRC patients with Notch signaling pathway mutation have better overall survival after immune checkpoint inhibitor treatment.

Low-dose orlistat promotes the therapeutic effect of oxaliplatin in colorectal cancer.

The failure of and resistance to oxaliplatin (OXA)-based chemotherapies may lead to poor prognosis in colorectal cancer (CRC) patients. It has been reported that orlistat (Orli) exhibits potent antitumor effects in several malignant tumors. Here, we identified that OXA in combination with low-dose Orli could sensitize CRC cells to OXA and induce marked synergistic apoptosis in vitro and in vivo. The potential synergistic effects were confirmed and quantified by in silico analysis. Furthermore, we validated the synergistic anti-tumor effects in CRC PDX mice model. A qPCR array was performed to evaluate the changes in 85 apoptosis-related genes to elucidate the possible molecular mechanisms in combination-induced cytotoxicity. To conclude, the antitumor synergistic effects of OXA and Orli make them effective and promising candidates for cancer treatment.