Colorectal cancer (CRC) is one of the most common types of malignancy worldwide. Distant metastasis is a key cause of CRC-associated mortality. MEIS2 has been identified to be dysregulated in several types of human cancer. However, the mechanisms underlying the regulatory role of MEIS2 in CRC metastasis remain largely unknown. For the first time, the present study demonstrated that MEIS2 serves a role as a promoter of metastasis in CRC. In vivo and in vitro experiments revealed that knockdown of MEIS2 significantly suppressed CRC migration, invasion and the epithelial-mesenchymal transition. Furthermore, microarray and bioinformatics analyses were performed to investigate the underlying mechanisms of MEIS2 in the regulation of CRC metastasis. Additionally, it was identified that a high expression of MEIS2 was significantly associated with a shorter overall survival time for patients with CRC. The present study demonstrated that MEIS2 may serve as a novel biomarker for CRC.

Heat shock factor 1 (HSF1) is a powerful multifaceted oncogenic modifier that plays a role in maintaining the protein balance of cancer cells under various stresses. In recent studies, there have been reports of increased expression of HSF1 in colorectal cancer (CRC) cells, and the depletion of the HSF1 gene knockdown has inhibited colon cancer growth both in vivo and in vitro. Therefore, HSF1 is a promising target for colon cancer treatment and chemoprevention. In the present study, we found that Schizandrin A (Sch A) significantly inhibited the growth of CRC cell lines by inducing cell cycle arrest, apoptosis and death. Through HSE luciferase reporter assay and quantitative PCR (qPCR), we identified Sch A as a novel HSF1 inhibitor. In addition, Sch A could effectively inhibit the induction of HSF1 target proteins such as heat-shock protein (HSP) 70 (HSP70) and HSP27, whether in heat shock or normal temperature culture. In the Surface Plasmon Resonance (SPR) experiment, Sch A showed moderate affinity with HSF1, further confirming that Sch A might be a direct HSF1 inhibitor. The molecular docking and molecular dynamic simulation results of HSF1/Sch A suggested that Sch A formed key hydrogen bond and hydrophobic interactions with HSF1, which may contribute to its potent HSF1 inhibition. These findings provide clues for the design of novel HSF1 inhibitors and drug candidates for colon cancer treatment.

Supplemental Digital Content is available in the text

No abstract

Objective: To develop an integrative model with clinical, pathological, and radiomic characteristics to predict the status of microsatellite instability (MSI) in rectal carcinoma (RC). Methods: A cohort of 788 RCs with 97 high MSI status (MSI-H) and 691 microsatellite stable status (MSS) were enrolled. The clinical and pathological characteristics were recorded. The radiomic features were calculated after segmentation of volume of interests and then patients were divided into the training set and validation set with a random proportion of 7:3. The logistic models of simple clinical characteristics (LM-Clin), pathological characteristics (LM-Patho), and radiomic features (LM-Radio) were constructed to distinguish MSI-H from MSS. The relevant radiomic score was calculated. Finally, a integrative nomogram (LM-Nomo) including significant clinical, pathological characteristics, and radiomics was developed. The area under receiver operator curve (AUC) was calculated to evaluate the efficacy of prediction. Results: The AUC of simple LM-Clin including variables of CEA and hypertension and LM-Patho including characteristics of gross type and lymph node metastasis ratio (LNR) was 0.584 (95%CI, 0.549-0.619) and 0.585 (95%CI, 0.550-0.619), which was lower than that of LM-Radio including 12 radiomic features with AUC of 0.737 (95%CI, 0.675-0.799). The LM-Nomo contained CEA, hypertension, LNR, and radiomic score, and the AUC was 0.757 (95%CI, 0.726-0.787). Conclusion: The AUCs of LM-Clin and LM-Patho were disappointing and lower than that of LM-Radio. The LM-Nomo demonstrated the best performance in predicting MSI-H status.

Colorectal cancer is one of the common malignant tumors in the digestive system, with high incidence and mortality rate. Therefore, there is an urgent need to identify and develop new molecular targets for colorectal cancer treatment. Previous studies have pointed out the important role of HMGB3 in tumors, and how it works in colorectal cancer needs to be studied in depth. In this study, we found that HMGB3 was highly expressed in COAD in the cBioPortal and GEPIA2 databases. Kaplan-Meier analysis showed that compared with patients with lower HMGB3 levels, patients with higher HMGB3 levels had poorer OS (p = 0.001). We also found a correlation between HMGB3 expression and immune infiltration of CRC. To investigate the mechanism of HMGB3 knockdown-mediated colorectal cancer inhibition, we detected a downregulation of N-cadherin, Vimentin and β-catenin proteins after knockdown of HMGB3. Taken together, HMGB3 can be an effective target for CRC treatment in the future, and we have reason to believe that HMGB3 will be of greater value in more tumors in the near future.

Immune subtyping is an important way to reveal immune heterogeneity, which may contribute to the diversity of the progression and treatment in head and neck squamous cell carcinoma (HNSCC). However, reported immune subtypes mainly focus on levels of immune infiltration and are mostly based on a mono-omics profile. This study aimed to identify a comprehensive immune subtype for HNSCC via multi-omics clustering and build a novel subtype prediction system for clinical application. Data were obtained from The Cancer Genome Atlas database and our independent multicenter cohort. Multi-omics clustering was performed to identify 3 clusters of 499 patients in The Cancer Genome Atlas based on immune-related gene expression and somatic mutations. The immune characteristics and biological features of the obtained clusters were revealed by bioinformatics, and 3 immune subtypes were identified: 1) adaptive immune activation subtype predominantly enriched in T cells, 2) innate immune activation subtype predominantly enriched in macrophages, and 3) immune desert subtype. Subsequently, the clinical implications of each subtype were analyzed per clinical epidemiology. We found that adaptive immune activation showed better survival outcomes and had a similar response to chemotherapy with innate immune activation, whereas immune desert might be relatively resistant to chemotherapy. Moreover, a subtype prediction system was developed by deep learning with whole slide images and named HISMD: HNSCC Immune Subtypes via Multi-omics and Deep Learning. We endowed HISMD with interpretability through image-based key feature extraction. The clinical implications, biological significances, and predictive stability of HISMD were successfully verified by using our independent multicenter cohort data set. In summary, this study revealed the immune heterogeneity of HNSCC and obtained a novel, highly accurate, and interpretable immune subtyping prediction system. For clinical implementation in the future, additional validation and utility studies are warranted.

Hypoxia-mediated tumor progression is a major problem in colorectal cancer (CRC). MicroRNA (miR)-200b-3p can attenuate tumorigenesis in CRC, while exosomal miRNAs derived from cancer-associated fibroblasts (CAFs) can promote cancer progression. Nevertheless, the function of exosomal miR-200b-3p derived from CAFs in CRC remains unclear. In this study, CAFs and normal fibroblasts (NFs) were isolated from CRC and adjacent normal tissues. Next, exosomes were isolated from the supernatants of CAFs cultured under normoxia and hypoxia. Cell viability was tested using the cell counting kit-8 assay, and flow cytometry was used to assess cell apoptosis. Cell invasion and migration were evaluated using the transwell assay. Dual-luciferase was used to investigate the relationship between miR-200b-3p and high-mobility group box 3 (HMBG3). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the miR-200b-3p and HMBG3 level. Our results found that the miR-200b-3p level was sharply reduced in CRC tissues compared to adjacent normal tissues. Additionally, the miR-200b-3p level was reduced in exosomes derived from hypoxic CAFs compared to exosomes derived from CAFs under normoxia. Exosomes derived from hypoxic CAFs weakened the sensitivity of CRC cells to 5-fluorouracil (5-FU) compared to hypoxic CAFs-derived exosomes. However, hypoxic CAFs-derived exosomes with upregulated miR-200b-3p increased the sensitivity of CRC cells to 5-fluorouracil (5-FU) compared to hypoxic CAFs-derived exosomes. In addition, HMBG3 was identified as the downstream target of miR-200b-3p in CRC cells, and its overexpression partially reversed the anti-tumor effect of the miR-200b-3p agomir on CRC via the mediation of the β-catenin/c-Myc axis. Furthermore, compared to exosomes derived from normoxia CAFs, exosomes derived from hypoxic CAFs weakened the therapeutic effects of 5-FU on CRC in vivo via the upregulation of HMGB3 levels. Collectively, the loss of exosomal miR-200b-3p in hypoxia CAFs reduced the sensitivity to 5-FU in CRC by targeting HMGB3. Thus, our research outlines a novel method for the treatment of CRC.