The diverse expression pattern of CD36 reflects its multiple cellular functions. However, the roles of CD36 in colorectal cancer (CRC) remain unknown. Here, we discover that CD36 expression is progressively decreased from adenomas to carcinomas. CD36 loss predicts poor survival of CRC patients. In CRC cells, CD36 acts as a tumor suppressor and inhibits aerobic glycolysis in vitro and in vivo. Mechanically, CD36-Glypcian 4 (GPC4) interaction could promote the proteasome-dependent ubiquitination of GPC4, followed by inhibition of β-catenin/c-myc signaling and suppression of downstream glycolytic target genes GLUT1, HK2, PKM2 and LDHA. Moreover, disruption of CD36 in inflammation-induced CRC model as well as Apc^Min/+ mice model significantly increased colorectal tumorigenesis. Our results reveal a CD36-GPC4-β-catenin-c-myc signaling axis that regulates glycolysis in CRC development and may provide an intervention strategy for CRC prevention.

Background: Colorectal cancer liver metastasis (CRLM) is characterized by an immunosuppressive microenvironment and a blunted response to immunotherapy. Notably, tumor‐associated macrophages (TAMs) play a critical role in modulating immune responses and exhibit significant heterogeneity in CRLM. Sphingosine kinase 1 (SPHK1) serves as a pivotal kinase in maintaining the balance between ceramide and sphingosine‐1‐phosphate (S1P) levels. However, the effects of SPHK1 within TAMs on tumor immune evasion during CRLM remain elusive. This study aimed at investigating the role of TAM‐intrinsic SPHK1 in tumor immunosuppressive microenvironment in CRLM. Methods: SPHK1 expression levels in TAMs were estimated by immunofluorescence and bioinformatics analysis. Several animal models were established to elucidate the role of SPHK1 in tumor immunity reprogramming in vivo. Flow cytometry, cytokine assay, and transwell assay were conducted to investigate the effects of SPHK1 in TAMs in cell‐cell communication in vitro. RNA‐sequencing, Western blotting, and quantitative real‐time polymerase chain reaction were used to explore the molecular mechanism by which SPHK1 activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in TAMs. Results: We found that SPHK1 was mainly expressed in TAMs and identified SPHK1 ⁺ TAMs as associated with CRLM and diminished efficacy of immunotherapy in human patients. These SPHK1 ⁺ TAMs exhibited strong immunosuppressive activities by inducing CD8 ⁺ T cell exhaustion with high programmed cell death 1 (PD‐1) expression via the interaction between TAMs and CRC cells. Mechanistically, SPHK1‐produced S1P exerted an autocrine effect to activate NLRP3 inflammasome and interleukin 1 beta (IL‐1β) release via nuclear factor‐kappa B (NF‐κB) and hypoxia inducible factor 1 subunit alpha (HIF‐1α) signaling in TAMs. Paracrine IL‐1β then upregulated the expression of monocyte chemoattractants and ADAM metallopeptidase domain 17 (ADAM17) sheddase in CRC cells, resulting in TAM infiltration and CD8 ⁺ T cell dysfunction in the liver microenvironment. Furthermore, combining SPHK1‐targeting treatments with anti‐PD‐1 therapy or radioimmunotherapy largely stalled liver metastasis and caused a significant extension of lifespan in preclinical mouse models. Conclusions: Our findings highlighted the role of SPHK1 of TAMs in facilitating CRLM by promoting CD8 ⁺ T cell dysfunction and immunosuppressive microenvironment. Combining SPHK1 blockade with anti‐PD‐1 therapy may be a promising treatment regimen for patients with CRLM.

Identification of the interplay between SOX9 and S100P in the metastasis and invasion of colon carcinoma Identification of the interplay between SOX9 and S100P in the metastasis and invasion of colon carcinoma

Altered expressions of nonmuscle myosin IIA (NMIIA) have been observed in certain types of cancers, but the impact of the alterations in gastric cancer (GC) remains unclear. The purpose of this study was to evaluate the expression of NMIIA at the mRNA and protein level in patients with GC and to assess its clinical significance. We investigated the expression of NMIIA in fresh, paired GC tissues by reverse transcriptase polymerase chain reaction (RT-PCR; n = 14) and Western blot analysis (n = 36). Simultaneously, we performed immunohistochemistry (IHC) on paraffin embedded specimens, including 96 GC specimens, 30 matched normal specimens and 30 paired metastatic lymph node samples. NMIIA is overexpressed in GC compared with the adjacent normal gastric epithelium (p < 0.001) and high-level NMIIA expression is significantly correlated with the depth of wall invasion, lymph node metastasis, distant metastasis and Tumor Node Metastasis (TNM) stage. Furthermore, elevated NMIIA expression is an independent prognostic factor in multivariate analysis using the Cox regression model (p = 0.021). These findings indicate that overexpression of NMIIA may contribute to the progression and poor prognosis of GC.

Aberrant gene expression plays critical roles in the development of colorectal cancer (CRC). Here we show that POTEE, which was identified as a member E of POTE ankyrin domain family, was significantly upregulated in colorectal tumors and predicted poor overall survival of CRC patients. In CRC cells, POTEE could act as an oncogene and could promote cell growth, cell-cycle progression, inhibit apoptosis, and elevates xenograft tumor growth. Mechanically, we used microarray analysis and identified a POTEE/SPHK1/p65 signaling axis, which affected the biological functions of CRC cells. Further evaluation showed that overexpression of POTEE could increase the protein expression of SPHK1, followed by promoting the phosphorylation and activation of p65 protein. Altogether, our findings suggested a POTEE/SPHK1/p65 signaling axis could promote colorectal tumorigenesis and POTEE might potentially serve as a novel biomarker for the diagnosis and an intervention of colorectal cancer.

Background: SLC2A5 is a high-affinity fructose transporter, which is frequently upregulated in multiple human malignant tumours. However, the function and molecular mechanism of SLC2A5 in colorectal cancer (CRC) remain unknown.Methods: We detected the expression levels of SLC2A5 in CRC tissues and CRC cell lines by western blotting, qRT-PCR and immunohistochemistry. CRC cell lines with stable overexpression or knockdown of SLC2A5 were constructed to evaluate the functional roles of SLC2A5 in vitro through conventional assays. An intrasplenic inoculation model was established in mice to investigate the effect of SLC2A5 in promoting metastasis in vivo. Methylation mass spectrometry sequencing, methylation specific PCR, bisulphite sequencing PCR, ChIP-qPCR and luciferase reporter assay were performed to investigate the molecular mechanism underlying transcriptional activation of SLC2A5.Results: We found that SLC2A5 was upregulated in colorectal tumour tissues. Functionally, a high level of SLC2A5 expression was associated with increased invasion and metastasis capacities of CRC cells both in vitro and in vivo. Mechanistically, we unveiled that S100P could integrate to a specific region of SLC2A5 promoter, thereby reducing its methylation levels and activating SLC2A5 transcription.Conclusions: Our results reveal a novel mechanism that S100P mediates the promoter demethylation and transcription activation of SLC2A5, thereby promoting the metastasis of CRC.