Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival.

BACKGROUND: Microsatellite instability-high (MSI-H) tumour patients generally have a better prognosis than microsatellite-stable (MSS) ones due to the large number of non-synonymous mutations. However, an increasing number of studies have revealed that less than half of MSI-H patients gain survival benefits or symptom alleviation from immune checkpoint-blockade treatment. Thus, an in-depth inspection of heterogeneous MSI-H tumours is urgently required. METHODS: Here, we used non-negative matrix factorisation (non-NMF)-based consensus clustering to define stomach adenocarcinoma (STAD) MSI-H subtypes in samples from The Cancer Genome Atlas and an Asian cohort, GSE62254. RESULTS: MSI-H STAD samples are basically clustered into two subgroups (MSI-H1 and MSI-H2). Further examination of the immune landscape showed that immune suppression factors were enriched in the MSI-H1 subgroup, which may be associated with the poor prognosis in this subgroup. CONCLUSIONS: Our results illustrate the genetic heterogeneity within MSI-H STADs, with important implications for cancer patient risk stratification, prognosis and treatment.

Pan-cancer analyses demonstrate that ANKRD6 is associated with a poor prognosis and correlates with M2 macrophage infiltration in colon cancer.

OBJECTIVE: Ankyrin repeat domain-containing protein 6 (ANKRD6) is an ankyrin repeat-containing protein which is structurally related to vertebrate inversin and Drosophila Diego. However, the correlations between ANKRD6 and tumor-infiltrating immune cells in cancers is not clear. METHODS: ANKRD6 expression was analyzed by Oncomine, Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). PrognoScan and GEPIA were used to evaluate the influence of ANKRD6 on clinical prognosis. TIMER and CIBERSORT were used to analyze correlations between ANKRD6 expression levels and tumor immune cell infiltrates. Immunohistochemical analysis of the relationship between ANKRD6 expression and overall survival, as well as the relationship between ANKRD6 expression and M2 macrophage infiltration, was performed. RESULTS: High level of ANKRD6 expression was associated with poor prognosis of colon cancer. ANKRD6 expression level was positively correlated with infiltrating levels of CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in colon cancer by using TIMER. Using CIBERSORT, we found that in plasma cells, CD8+ T cells, CD4+ memory resting T cells, follicular helper T cells and activated natural killer cells were significantly lower in the ANKRD6-high group than in the ANKRD6-low group. M0 and M2 macrophages were significantly higher in the ANKRD6-high group than in the ANKRD6-low group. Immunohistochemistry confirmed that M2 macrophage infiltration in the ANKRD6-high group significantly increased. CONCLUSIONS: The high ANKRD6 expression is associated with poor prognosis of colon cancer. ANKRD6 expression is positively correlated with M2 macrophage infiltration in colon cancer.

High-risk Stage III colon cancer patients identified by a novel five-gene mutational signature are characterized by upregulation of IL-23A and gut bacterial translocation of the tumor microenvironment.

The heterogeneities of colorectal cancer (CRC) lead to staging inadequately of patients' prognosis. Here, we performed a prognostic analysis based on the tumor mutational profile and explored the characteristics of the high-risk tumors. We sequenced 338 colorectal carcinomas as the training dataset, constructed a novel five-gene (SMAD4, MUC16, COL6A3, FLG and LRP1B) prognostic signature, and validated it in an independent dataset from The Cancer Genome Atlas (TCGA). Kaplan-Meier and Cox regression analyses confirmed that the five-gene signature is an independent predictor of recurrence and prognosis in patients with Stage III colon cancer. The mutant signature translated to an increased risk of death (hazard ratio = 2.45, 95% confidence interval = 1.15-5.22, p = 0.016 in our dataset; hazard ratio = 4.78, 95% confidence interval = 1.33-17.16, p = 0.008 in TCGA dataset). RNA and bacterial 16S rRNA sequencing of high-risk tumors indicated that mutations of the five-gene signature may lead to intestinal barrier integrity, translocation of gut bacteria and deregulation of immune response and extracellular related genes. The high-risk tumors overexpressed IL23A and IL1RN genes and enriched with cancer-related bacteria (Bacteroides fragilis,Peptostreptococcus, Parvimonas, Alloprevotella and Gemella) compared to the low-risk tumors. The signature identified the high-risk group characterized by gut bacterial translocation and upregulation of interleukins of the tumor microenvironment, which was worth further researching.

Deciphering molecular properties of hypermutated gastrointestinal cancer.

Great mutational heterogeneity is observed both across cancer types (>1000-fold) and within a given cancer type, with a fraction harboring >10 mutations per million bases, thus termed hypermutation. We determined the genome-wide effects of high mutation load on the transcriptome and methylome of two cancer types; namely, colorectal cancer (CRC) and stomach adenocarcinoma (STAD). Briefly, hierarchical clustering of the expression and methylation profiles showed that the majority of CRC and STAD hypermutated samples were mixed and separated from their respective non-hypermutated samples, exceeding the boundary of tissue specificity. Further in-detailed exploration uncovered that the underlying molecular mechanism may be related to the perturbation of chromatin remodeling genes.

Subtyping of microsatellite instability-high colorectal cancer.

BACKGROUND: Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) generally have a better prognosis than patients with microsatellite stable (MSS) CRC. However, some MSI-H CRC patients do not gain overall survival benefits from immune checkpoint-blockade treatment. In other words, heterogeneity within the subgroup of MSI-H tumors remains poorly understood. Thus, an in-depth molecular characterization of MSI-H tumors is urgently required. METHODS: Here, we use nonnegative matrix factorization (NMF)-based consensus clustering to define CRC MSI-H subtypes in The Cancer Genome Atlas and a French multicenter cohort GSE39582. CIBERSORT was used to calculate the proportions of 22 lymphocytes in tumor tissue in MSI-H subtypes. RESULTS: MSI-H CRC samples basically clustered into two subgroups (MSI-H1 and MSI-H2). MSI-H1 was characterized by a lower BRAF mutational status, higher frequency of chromosomal instability, global hypomethylation, and worse survival than MSI-H2. Further examination of the immune landscape showed that macrophages of the M2 phenotype were enriched in MSI-H1, which may be associated with poor prognosis in this subgroup. CONCLUSIONS: Our results illustrate the genetic heterogeneity in MSI-H CRCs and macrophages may serve as good targets for anticancer therapy in MSI-H1.

Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis.

Liver metastases develop in more than half of the patients with colorectal cancer (CRC) and are associated with a poor prognosis. The factors influencing liver metastasis of CRC are poorly characterized, but this information is urgently needed. We have now discovered that small extracellular vesicles (sEVs; exosomes) derived from CRC can be specifically targeted to liver tissue and induce liver macrophage polarization toward an interleukin-6 (IL-6)-secreting proinflammatory phenotype. More importantly, we found that microRNA-21-5p (miR-21) was highly enriched in CRC-derived sEVs and was essential for creating a liver proinflammatory phenotype and liver metastasis of CRC. Silencing either miR-21 in CRC-sEVs or Toll-like receptor 7 (TLR7) in macrophages, to which miR-21 binds, abolished CRC-sEVs' induction of proinflammatory macrophages. Furthermore, miR-21 expression in plasma-derived sEVs was positively correlated with liver metastasis in CRC patients. Collectively, our data demonstrate a pivotal role of CRC-sEVs in promoting liver metastasis by inducing an inflammatory premetastatic niche through the miR-21-TLR7-IL-6 axis. Thus, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis.

CLCA1 suppresses colorectal cancer aggressiveness via inhibition of the Wnt/beta-catenin signaling pathway.

BACKGROUND: Chloride channel accessory 1 (CLCA1) belongs to the calcium-sensitive chloride conductance protein family, which is mainly expressed in the colon, small intestine and appendix. This study was conducted to investigate the functions and mechanisms of CLCA1 in colorectal cancer (CRC). METHODS: The CLCA1 protein expression level in CRC patients was evaluated by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and western blotting analysis. Using CRISPR/Cas9 technology, CLCA1-upregulated (CLCA1-ACT) and CLCA1-knockout cells (CLCA1-KO), as well as their respective negative controls (CLCA1-ACT-NC and CLCA1-KO-NC), were constructed from the SW620 cell line. Cell growth and metastatic ability were assessed both in vitro and in vivo. The association of CLCA1 with epithelial-mesenchymal transition (EMT) and other signaling pathways was determined by western blotting assays. RESULTS: The expression level of CLCA1 in CRC tissues was significantly decreased compared with that in adjacent normal tissue (P< 0.05). Meanwhile, the serum concentration of CLCA1 in CRC patients was also significantly lower when compared with that of healthy controls (1.48 ± 1.06 ng/mL vs 1.06 ± 0.73 ng/mL, P = 0.0018). In addition, CLCA1 serum concentration and mRNA expression level in CRC tissues were inversely correlated with CRC metastasis and tumor stage. Upregulated CLCA1 suppressed CRC growth and metastasis in vitro and in vivo, whereas inhibition of CLCA1 led to the opposite results. Increased expression levels of CLCA1 could repress Wnt signaling and the EMT process in CRC cells. CONCLUSIONS: Our findings suggest that increased expression levels of CLCA1 can suppress CRC aggressiveness. CLCA1 functions as a tumor suppressor possibly via inhibition of the Wnt/beta-catenin signaling pathway and the EMT process.

Dynamics of chloroplast genomes in green plants.

Chloroplasts are essential organelles, in which genes have widely been used in the phylogenetic analysis of green plants. Here, we took advantage of the breadth of plastid genomes (cpDNAs) sequenced species to investigate their dynamic changes. Our study showed that gene rearrangements occurred more frequently in the cpDNAs of green algae than in land plants. Phylogenetic trees were generated using 55 conserved protein-coding genes including 33 genes for photosynthesis, 16 ribosomal protein genes and 6 other genes, which supported the monophyletic evolution of vascular plants, land plants, seed plants, and angiosperms. Moreover, we could show that seed plants were more closely related to bryophytes rather than pteridophytes. Furthermore, the substitution rate for cpDNA genes was calculated to be 3.3×10(-10), which was almost 10 times lower than genes of nuclear genomes, probably because of the plastid homologous recombination machinery.

MicroRNA mediates DNA methylation of target genes.

Small RNAs represented by microRNA (miRNA) plays important roles in plant development and responds to biotic and abiotic stresses. Previous studies have placed special emphasis on gene-repression mediated by miRNA. In this work, the DNA methylation pattern of microRNA genes (MIRs) was interrogated. Full-length cDNA and EST were used to confirm the entity of pri-miRNA. In parallel, miRNA in 24 nucleotides (nt) was pooled to detect chromatin modification effect by using bisulfite sequencing data. 97 MIRs were supported by full-length cDNA and 30 more were hit by EST. Notably, methylation levels of conserved MIRs were significantly lower than the non-conserved at all contexts (CG, CHG, and CHH). Additionally, a substantial part of 24-nt miRNA was able to induce target site methylation, providing a broader perspective for researchers.

CPuORF correlates with miRNA responsive elements on protein evolutionary rates.

miRNA is increasingly being recognized as a key regulator of metabolism in animals. A wealth of evidence has suggested that miRNA mainly binds 3' UTR of mRNA and modulates the cell activities via repressing the mRNA translation. However, as the translation initiates at 5' UTR, cis elements like upstream open reading frame (uORF) resided in 5' UTR may also affect the translation efficiency or elongation. In this study, we performed a systematic analysis of miRNA responsive elements (MREs) and uORF of the same transcript in three model organisms (human, mouse, and Drosophila). Intriguingly, we found that the 3' UTR length grew with the complexity of species (human>mouse>Drosophila), in sharp contrast with the invariability of 5' UTR. Additionally, MRE number correlated well with the 3' UTR length, while uORF number showed a weak correlation with the 5' UTR length. Further, we found that human genes with conserved peptide upstream open reading frame (CPuORF) tend to have more MREs and lower evolutionary rates, which provides new insights into the correlation between UTR properties and translational control in animals.

Flexible microRNA arm selection in rice.

MicroRNAs act at the post-transcriptional level and guide Argonaute proteins to cleave their corresponding target transcripts. However, little attention has been paid to arm selection in miRNA precursors. In this study, small RNA high-throughput sequencing data from 29 different rice libraries were pooled to investigate tissue- and abiotic stress-specific dynamic expression of miRNAs. We found that more than half of pre-miRNAs showed changes in arm selection in different tissues and/or under different abiotic stresses. Our findings suggest that miRNA selection is remarkably prevalent in plants, providing new insights into the role of miRNAs in plant growth and development.

miR-433 Inhibits Glioblastoma Progression by Suppressing the PI3K/Akt Signaling Pathway Through Direct Targeting of ERBB4.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor where new biomarkers and drug targets are much needed in the oncology clinic. miR-433 was identified as a tumor-suppressing miRNA in several different types of human cancer. However, the integrative biology of miR-433 in GBM is still largely unknown. By analyzing the expression profiles of miR-433 in 198 patients with glioma at The Cancer Genome Atlas, we found that the miR-433 expression was decreased in glioma whereas the low expression of miR-433 was significantly associated with shorter overall survival. We then conducted in vitro studies and demonstrated that increased expression of miR-433 suppressed the proliferation, migration, and invasion of LN229 and T98G cells, two representative glioma cell lines. Further, using in vivo mouse model, we found that upregulation of miR-433 inhibited the tumor growth of glioma cells. To situate the integrative biology understanding of the action of miR-433 in glioma, we identified ERBB4 as a gene targeted directly by miR-433 in LN229 and T98G cells. Overexpressed ERBB4 rescued the phenotype caused by overexpression of miR-433. Finally, we showed that miR-433 suppressed the PI3K/Akt pathway in glioma cells. In conclusion, our study demonstrated that miR-433 could potentially act as a tumor suppressor for GBM and may serve as a potential therapeutic target for GBM. Further integrative biology and clinical translational research are warranted to evaluate miR-433 in GBM.

Stromal score is a promising index in tumor patients' outcome determination.

Background: Immune status is widely acknowledged as a valuable marker for predicting cancer prognosis and therapy response. However, there has been a limited understanding of the stromal landscape in cancer. Methods: By employing ESTIMATE, stromal- and immune-scores were inferred for 6193 tumor samples spanning 12 cancer types sourced from The Cancer Genome Atlas (TCGA). Subsequently, the samples were categorized into seven groups based on their stromal and immune scores. A comparison of prognosis, lymphocyte and stromal cell infiltration, and the response to programmed death ligand 1 (PD-L1) therapy was conducted among these subtypes. Results: It was unveiled by the analysis that, in the majority of cancer types, stromal score exhibited a more potent predictive capability for outcomes compared to the immune score. Furthermore, it was observed that in four cancer types, intermediate immune infiltration coupled with low stromal infiltration correlated with the most favorable overall survival, whereas an unfavorable outcome was predicted in colorectal cancer (CRC) and stomach adenocarcinoma (STAD) when high immune infiltration coexisted with intermediate or high stromal infiltration. Conclusion: In summary, while high immune scores frequently correlate with a positive prognosis, such correlation is not universal. A potential strategy to address the current limitations of the immune score in specific circumstances could involve a focus on stromal scores or a subtle integration of stromal and immune status.

Association Mining Identifies MAL2 as a Novel Tumor Suppressor in Colorectal Cancer.

Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. However, the driver genes that promote CRC metastasis remain poorly understood. Association mining mines and extracts the repeated correlations and relevance in a dataset to predict the appearance of other data items according to the appearance of one item. Methods: Here, the Apriori algorithm was used to find the frequent mutational gene sets (FMGSs) and hidden association rules (ARs) within these FMGSs from 383 CRCs with whole exome sequencing datasets. The weighted correlation network analysis (WGCNA) was used to identify the hub genes in CRC. CCK8, colony formation, cell migration and invasion assays were adopted to detect the roles of hub genes in CRC. Results: Intriguingly, we found that MAL2 (myelin and lymphocyte protein 2) was associated with TP53 and APC in stage IV of CRC, and further subnetwork exploration based on WGCNA identified MAL2 as a potent hub gene. To validate the metastasis-related role of MAL2 in CRC, a lentivirus-based overexpression system was utilized to construct MAL2-overexpressing human CRC LOVO cells. Overexpression of MAL2 remarkably inhibited CRC cell proliferation and invasion. Conclusion: Our results highlighted that MAL2 acts as a tumor suppressor in CRC and could serve as a potential therapeutic target.

A pretreatment transcriptomic signature that predicts outcomes of immunotherapy in melanoma.

Identifying indicators of immunotherapy response are key to clinical treatment decisions. To date, immunotherapy is most widely used in melanoma because of its higher tumor mutation burden compared to other cancer types. However, less than half of melanoma patients can benefit from immune checkpoint inhibitor (ICI) therapy. For this reason, we deciphered pretreatment transcriptomes across a cohort of melanoma patients receiving anti-PD-1 or CTLA-4 alone (sICI) or in combination (cICI). We developed a two-gene signature that could predict the curative effect of ICI in melanoma by using the LASSO method. The pre-ICI signature displayed an equally competitive predictive power as the post-ICI irRECIST assessment that could offer clues regarding long-term ICI therapy response and facilitate risk stratification and treatment strategies.

Hypoxia Confers Tumor with a Higher Immune Infiltration but Lower Mutation Burden in Gastrointestinal Cancer.

Background: Hypoxia is one of the driving forces of cancer progression, recurrence, and metastasis. However, the association between the tumor hypoxic tumor microenvironment and the tumor mutation burden (TMB) is poorly understood in gastrointestinal cancer. Methods: Approximately 2,000 samples from colorectal cancer (CRC) and stomach adenocarcinoma (STAD) patients were obtained from the gene expression omnibus database and the cancer genome Atlas databases and were clustered and subtyped by nonnegative matrix factorization. Significant differentially expressed genes that were possibly related to survival differences between the hypoxic and normoxic groups were subjected to multivariate Cox regression. Results: Gastrointestinal cancer patients with CRC and STAD were further divided into two subgroups, namely, the hypoxia group and the normoxia group, and hypoxia was correlated with unfavorable outcomes. Notably, hypoxic tumors had lower TMB but significantly higher levels of immune and stromal infiltration. A signature of HEYL and NRP1 selected by LASSO classified gastrointestinal cancer patients into either a low or high-risk group, allowing for the combination of TMB status with markers of hypoxia in future clinical applications. Conclusions: Hypoxia is an independent prognostic factor and a strong immune infiltration indicator in gastrointestinal tumors of different organs, especially for cancers with low TMB.

Survival outcome and prognostic factors for colorectal cancer with synchronous bone metastasis: a population-based study.

Prognostic factors of synchronous bone metastatic colorectal cancer (CRC) are still undetermined. We aimed to investigate survival outcome and prognostic factors of patients with synchronous bone metastatic CRC. Information of patients with synchronous bone metastatic CRC were obtained from the Surveillance, Epidemiology, and End Results (SEER) and West China Hospital (WCH) databases. Cases from SEER database composed construction cohort, while cases from WCH database were used as validation cohort. A novel nomogram was constructed to predict individual survival probability based on Cox regression model. The performance of the nomogram was internally and externally validated using calibration curves and concordance index (C-index). Three hundred and eighty-one patients from SEER database were eligible. The median disease specific OS was 9.0 months (95% confidence interval [CI]: 7.3-10.7 months). Multivariate Cox analysis identified seven independent prognostic factors including histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis. A novel nomogram was established based on these variables. In the internal validation, the C-index (0.72, 95% CI 0.69-0.75) and calibration curve indicated well performance of this nomogram at predicting survival outcome in bone metastatic CRC. In the external validation, the C-index was 0.57 (95% CI 0.46-0.68). The prognosis of synchronous bone metastatic CRC is very poor. Histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis are independent prognostic factors. Further study is warranted to confirm the practicality of the prognostic nomogram.

Hypermutated tumours across 11 cancer types show three distinct immune subtypes.

BACKGROUND: Complete remission is observed in less than half of hypermutated (HM) tumours after immune checkpoint blockade therapy, indicating that HM tumours are very heterogeneous. Thus, there is an urgent requirement to decipher the unknown intrinsic HM tumour subtypes. METHODS: Statistical analysis was performed on somatic mutation data from 5519 tumours across 11 cancer types obtained from The Cancer Genome Atlas and 338 colorectal cancer (CRC) samples obtained from an Asian cohort. Samples with a tumour mutation burden >10 mut/Mb were classified as HM. A total of 1040 HM samples harbouring corresponding transcriptomes were used for non-negative matrix factorisation clustering. Tumour mutational burden, neoantigens, T cell receptor (TCR) diversity, stromal score and immune score were compared between the subtypes. RESULTS: HM tumours fell into three distinct immune subtypes: HM1, HM2 and HM3. HM3 tumours were correlated with increased CD8 T cell infiltration, high TCR diversity, a high immune score and prolonged survival. HM2 tumours were correlated with an abundant stromal component, epithelial-mesenchymal transition, TGFß, angiogenesis hallmarks and poor outcomes. The infiltration of more CD8 T cells and increased chemokine expression in HM3 were validated in CRC by immunofluorescence. CONCLUSIONS: These findings will facilitate the development of a subtype-oriented therapy strategy to enhance the treatment effect in the near future.

The Effects of Differentially-Expressed Homeobox Family Genes on the Prognosis and HOXC6 on Immune Microenvironment Orchestration in Colorectal Cancer.

Background: The homeobox (HOX) gene family encodes highly conserved transcription factors, that play important roles in the morphogenesis and embryonic development of vertebrates. Mammals have four similar HOX gene clusters, HOXA, HOXB, HOXC, and HOXD, which are located on chromosomes 7, 17,12 and 2 and consist of 38 genes. Some of these genes were found to be significantly related to a variety of tumors; however, it remains unknown whether abnormal expression of the HOX gene family affects prognosis and the tumor microenvironment (TME) reshaping in colorectal cancer (CRC). Therefore, we conducted this systematic exploration to provide additional information for the above questions. Methods: RNA sequencing data from The Cancer Genome Atlas (TCGA) and mRNA expression data from Gene Expression Omnibus (GEO) combined with online tumor analysis databases (UALCAN, TIMER, PrognoScan) were utilized to explore the relationship among abnormal expression of HOX family genes, prognosis and the tumor immune microenvironment in CRC. Results: 1. Differential expression and prognosis analysis: 24 genes were significantly differentially expressed in CRC compared to adjacent normal tissues, and seven upregulated genes were significantly associated with poor survival. Among these seven genes, univariate and multivariate Cox regression analysis revealed that only high expression of HOXC6 significantly contributed to poor prognosis; 2. The influence of overexpressed HOXC6 on the pathway and TME: High HOXC6 expression was significantly related to the cytokine pathway and expression of T cell attraction chemokines, the infiltration ratio of immune cells, expression of immune checkpoint markers, tumor mutation burden (TMB) scores and microsatellite instability-high (MSI-H) scores; 3. Stratified analysis based on stages: In stage IV, HOXC6 overexpression had no significant impact on TMB, MSI-H, infiltration ratio of immune cells and response prediction of immune checkpoint blockers (ICBs), which contributed to significantly poor overall survival (OS). Conclusion: Seven differentially expressed HOX family genes had significantly worse prognoses. Among them, overexpressed HOXC6 contributed the most to poor OS. High expression of HOXC6 was significantly associated with high immunogenicity in nonmetastatic CRC. Further research on HOXC6 is therefore worthwhile to provide potential alternatives in CRC immunotherapy.

HomeoboxC6 promotes metastasis by orchestrating the DKK1/Wnt/ß-catenin axis in right-sided colon cancer.

Patients with right-sided colon cancer (RCC) generally have a poorer prognosis than those with left-sided colon cancer (LCC). We previously found that homeobox C6 (HOXC6) was the most significantly upregulated gene in RCC compared to LCC. However, it remains unclear whether HOXC6 plays a role in tumor proliferation and metastasis. Our study aimed to explore the potential oncogenic role and the detailed molecular mechanism of HOXC6 in RCC. In this study, HOXC6 was validated to be overexpressed in RCC and associated with poor prognosis. Furthermore, overexpression of HOXC6 promoted the migration and invasion of colon cancer cells through inducing EMT by activating the Wnt/ß-catenin signaling pathway and inhibition of DKK1 secretion. Lastly, we preliminary explored the translational effect of HOXC6 and found that silencing of HOXC6 made HCT116 and HT29 cells more sensitive to irinotecan.