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Bone metastasis (BM) can obviously affect the quality of life of patients in colorectal cancer (CRC), and the whole management of patients with BM would be attractive in current clinical practice. A total of 52,859 patients during 2010–2015 were collected from Surveillance, Epidemiology, and End Results (SEER) database. After propensity score matching (PSM), cancer-specific survival (CCS) and overall survival (OS) with BM were adopted to assess survival probability difference. Logistic regression was used to identify risk factors for BM; COX proportion hazard regression was applied to explore prognosticators for OS in patients with BM. Subsequently, nomograms were constructed and receiver operating curves (ROCs) were used to confirm the validation of nomogram. Three hundred and forty-two (0.65%) patients were diagnosed with synchronous BM. After PSM, 16 variables were balanced. Tumor site, histology, grade, T stage, N stage, CEA, radiochemotherapy, surgery, and liver/lung/brain metastases were associated with BM, and histology, grade, T stage, N stage, CEA, chemotherapy, surgery, and liver/lung metastases were prognosticators for BM survival. Nomograms were applied and the ROC curve proved the predictive effects. CRC patients with BM have worse real-world survival. Nomogram can predict incidence of BM in CRC patients and survival among patients with BM.

Background Necroptosis is a new form of programmed cell death that is associated with cancer initiation, progression, immunity, and chemoresistance. However, the roles of necroptosis-related genes (NRGs) in colorectal cancer (CRC) have not been explored comprehensively. Methods In this study, we obtained NRGs and performed consensus molecular subtyping by “ConsensusClusterPlus” to determine necroptosis-related subtypes in CRC bulk transcriptomic data. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of different cell types in the tumor microenvironment (TME). Single-cell transcriptomic analysis was performed to confirm classification related to NRGs. NRG_score was developed to predict patients’ survival outcomes with low-throughput validation in a patients’ cohort from Fudan University Shanghai Cancer Center. Results We identified three distinct necroptosis-related classifications (NRCs) with discrepant clinical outcomes and biological functions. Characterization of TME revealed that there were two stable necroptosis-related phenotypes in CRC: a phenotype characterized by few TME cells infiltration but with EMT/TGF-pathways activation, and another phenotype recognized as immune-excluded. NRG_score for predicting survival outcomes was established and its predictive capability was verified. In addition, we found NRCs and NRG_score could be used for patient or drug selection when considering immunotherapy and chemotherapy. Conclusions Based on comprehensive analysis, we revealed the potential roles of NRGs in the TME, and their correlations with clinicopathological parameters and patients’ prognosis in CRC. These findings could enhance our understanding of the biological functions of necroptosis, which thus may aid in prognosis prediction, drug selection, and therapeutics development.

Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.

With emphasis of surgical management, the lymph node (LN) status has been advocated to predict prognosis in colon cancer with distant metastatic. Therefore, we tend to compare the prognostic performance of American Joint Committee on Cancer (AJCC) N-staging relative to lymph node ratio (LNR), log odds of metastatic lymph nodes (LODDS), and N-score in stage IV colon cancer. About 20,961 patients who underwent primary surgical resection for stage IV colon cancer were extracted from Surveillance, Epidemiology, and End Results (SEER) Program database. Harrell’s C statistic (C-index) and Akaike’s Information Criterion (AIC) were used to distinguish the prognostic performance of the different LN-staging schemes. Of the 20,961 patients, 17,043 (81.3%) had been with lymph node metastasis, and the median number of examined lymph nodes (ELNs) was 15. When assessed as continuous values, the LODDS shown as the best system with greatest discriminatory power (C-index, 0.6241; AIC, 29114.29) generally and each subgroups divided by ELNs. When modeled as categorical cutoff variables for further clinical usage, the 8th AJCC N-stage outperformed the other three schemes with either ELNs less than 12 (C-index, 0.5770; AIC, 8992.638), between 12 and 25 (C-index, 0.6084; AIC, 13905.72), or more than 25(C-index, 0.6192; AIC, 3138.018) with increasing C-index and less AIC value. When assessed as categorical variables, N-stage performed superiorly regardless of ELNs. When assessed as a continuous variable, LODDS exhibited good discriminative ability and goodness of fit in predicting survival for colon cancer patients regardless of ELNs.

The aim of this study is to evaluate the epidemiology of and prognostic factors for appendiceal carcinomas (ACs). All cases of ACs registered in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2014 were retrospectively identified in this study. Age-adjusted incidence and survival rates were calculated. We analyzed 7170 patients with ACs. We observed a significant increase in the reported annual age-adjusted incidence of ACs from 1973 (0.18/100,000) to 2014 (1.11/100,000). The elevation of the incidence was noted in all the histological types, stages, and grades. The most common histological type varied by race, with the appendiceal mucinous adenocarcinoma (AMA) being the most common in white, Asian/Pacific Islander, and American Indian/Alaskan Native patients, and the appendiceal adenocarcinoma (AA) being the most common in African American patients. In multivariate analysis of patients with all ACs, gender (P

Long noncoding RNAs (lncRNAs) have been revealed to play critical roles in tumor initiation and progression. The antisense lncRNA LDLRAD4-AS1 is the longest lncRNA of LDLRAD4, and its expression levels, cellular localization, precise function, and mechanism in colorectal cancer (CRC) remain unknown. In this study, we observed that lncRNA LDLRAD4-AS1 was located in the nucleus of CRC cells and that lncRNA LDLRAD4-AS1 was upregulated in most CRC specimens and cell lines. Overexpression of lncRNA LDLRAD4-AS1 was correlated with poor prognosis in CRC patients. LncRNA LDLRAD4-AS1 upregulation enhanced the migration and invasion of CRC cells in vitro and facilitated CRC metastasis in vivo. Mechanistic investigations suggested that lncRNA LDLRAD4-AS1 could decrease the expression of LDLRAD4 by disrupting the stability of LDLRAD4 mRNA, resulting in epithelial-to-mesenchymal transition (EMT) through upregulating Snail, thereby promoting metastasis in CRC. Our results demonstrated a previously unrecognized LDLRAD4-AS1-LDLRAD4-Snail regulatory axis involved in epigenetic and posttranscriptional regulation that contributes to CRC progression and metastasis.

Background Low expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients. However, the underlying mechanism remains unclear. Materials and methods The effects of FOXE1 on the growth of colon cancer cells and the expression of glycolytic enzymes were investigated in vitro and in vivo. Molecular biological experiments were used to reveal the underlying mechanisms of altered aerobic glycolysis. CRC tissue specimens were used to determine the clinical association of ectopic metabolism caused by dysregulated FOXE1. Results FOXE1 is highly expressed in normal colon tissues compared with cancer tissues and low expression of FOXE1 is significantly associated with poor prognosis of CRC patients. Silencing FOXE1 in CRC cell lines dramatically enhanced cell proliferation and colony formation and promoted glucose consumption and lactate production, while enforced expression of FOXE1 manifested the opposite effects. Mechanistically, FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription. Furthermore, the expression of FOXE1 in CRC tissues was negatively correlated with that of HK2. Conclusion FOXE1 functions as a critical tumor suppressor in regulating tumor growth and glycolysis via suppressing HK2 in CRC.

Homogeneous chitosan-silk fibroin/hydroxyapatite (CS-SF/HA) composites were prepared by in situ precipitation method driven by a multiple-order template. The morphology of the composites was investigated by scanning electron microscope (SEM) and transmission electron microscope (TEM). The compositional analysis was carried out by X-ray diffraction analysis (XRD) and Fourier transformed infrared spectroscopy (FTIR). The mechanical properties and biocompatibility of the composites were also determined. The results indicated that the inorganic particles of uniform size (50 nm) were well-dispersed among the CS-SF matrices. The compressive modulus of the CS-SF/HA composites was enhanced with the increasing amount of SF. The in vitro results suggested that the MC3T3-E1 osteoblast-like cells on CS-SF/HA composite disks displayed strong bonding and spreading, and the cell proliferation cultured on each composite disk increased throughout the culture period for up to 7 days. Especially, the samples with higher content of SF had much better biological properties. The evidences proved that the CS-SF/HA composites possessed excellent biocompatibility. By using the freeze-drying technique, hierarchical porous scaffolds with pores ranging from 50 μm to 200 μm were obtained. This work presented the advantages of in situ precipitation method to prepare the organic/inorganic composites, and a multiple-order template was introduced in the system to improve the properties of the composites by combining the merits of each organic template.