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Abstract: Colorectal cancer (CRC) has a high metastasis rate. MicroRNA (miRNA) is an epigenetic factor required to regulate cell proliferation, tumor cell growth, cancer formation, and metastasis by regulating tumor-suppressor genes or oncogenes. The objective of this study is to identify miRNAs and their target genes related to CRC migration and metastasis. Previously, we used miRNA microarray to reveal that miR-338-5p was significantly upregulated in patients with recurrent CRC. The expression level of miR-338-5p in tumor tissues of metastatic patients is higher than that in nonmetastatic patients. In this study, we report that miR-338-5p expression level was positively correlated with high migration activity of CRC cells. Overexpression of miR-338-5p induced the migration of CRC HCT-116 cells. Furthermore, overexpression of miR-338-5p inhibited its target gene phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) messenger RNA (mRNA) and protein expression in HCT-116 cells. Downregulation of miR-338-5p increased PIK3C3 mRNA and protein expression in CRC SW480 cells. Furthermore, our study results show that miR-338-5p blocked autophagy, as demonstrated by decreased LC3 type II expression. Autophagy inhibited the migration of colon cancer cell HCT-116 after rapamycin treatment. It can thus be concluded that miR-338-5p induces CRC cell migration by suppressing PIK3C3 expression and autophagy. [Copyright &y& Elsevier]

Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Approximately 40% of CRC patients are KRAS sequence variation, including KRAS G13D mutation (KRASG13D) CRC patients, accounting for approximately 8% of all KRAS mutations in CRC patients and showing little benefit from anti-EGFR therapy. Therefore, there is an urgent need for new and effective anticancer agents in patients with KRASG13D CRC. Here, we identified a natural product, erianin, that directly interacted with purified recombinant human KRASG13D with a Kd of 1.1163 μM, which also significantly improve the thermal stability of KRASG13D. The cell viability assay showed that KRASG13D cells were more sensitive to erianin than KRASWT or KRASG12V cells. In vitro , results showed that erianin suppressed the migration, invasion and epithelial-mesenchymal transition (EMT) of KRASG13D CRC cells. Furthermore, erianin induced ferroptosis, as evidenced by the accumulation of Fe2+ and reactive oxygen species (ROS), lipid peroxidation, and changes in the mitochondrial morphology of KRASG13D CRC cells. Interestingly, we also found that erianin-induced ferroptosis was accompanied by autophagy. Moreover, the occurrence of erianin-induced ferroptosis is reversed by autophagy inhibitors (NH4Cl and Bafilomycin A1) and ATG5 knockdown, suggesting that erianin-induced ferroptosis is autophagy-dependent. In addition, we evaluated the inhibition of tumor growth and metastasis by erianin in vivo using a subcutaneous tumor model and a spleen-liver metastasis model, respectively. Collectively, these data provide novel insights into the anticancer activity of erianin, which is valuable for the further discussion and investigation of the use of erianin in clinical anticancer chemotherapy for KRASG13D CRC. [Display omitted] • Erianin directly interacted with KRASG13D and markedly improve the thermal stability of KRASG13D protein in cells. • Erianin suppressed malignant behaviors and EMT through autophagy-dependent ferroptosis in KRASG13D CRC cells. • Erianin suppresses KRASG13D CRC tumor growth and metastasis in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Colorectal cancer (CRC) has high recurrence rate.Effective biomarkers for the detection of colon cancer are still unavailable. MicroRNA (miRNA) is an epigenetic factor that regulates cell proliferation, tumor cell growth, cancer formation, and metastasis by regulating tumor suppressor genes or oncogenes. miRNA has the potential to be used as a biomarker for the diagnosis of diverse cancers. Previously, we revealed that miR-139-3 p is downregulated and miR-338-5 p is upregulated in recurrent CRC patients. The present study further reveals that the miR-139-3 p expression level is inversely correlated with increased metastatic status in three colon cancer cell lines (SW480, SW620, and colo201), as determined using real-time polymerase chain reaction. Furthermore, in 51 pairs of CRC clinical specimens, the expression level of mir-139-3 p was significantly lower in the tumor sections than in the adjacent normal tissues (p < 0.0001), indicating that they are tumor-suppressive miRNAs. Furthermore, the expression level of mir-338-5 p in the tumor tissues of metastatic patients was significantly higher than in the tumor tissues of nonmetastatic patients (p < 0.05), indicating that mir-338-5 p is positively correlated with metastasis. All together, mir-139-3 p and mir-338-5 p may have potential use as biomarkers for the diagnosis of tumor formation and metastasis in CRC patients. [Copyright &y& Elsevier]

Gastrointestinal cancer causes countless deaths every year due to therapeutic resistance. However, whether metabolic alterations contribute to chemoresistance is not well understood. In this study, we report that fatty acid (FA) catabolism was activated in gastrointestinal cancer cells treated with oxaliplatin, which exhibited higher expression of the rate-limiting enzymes carnitine palmitoyltransferase 1B (CPT1B) and CPT2. The clinical analysis also showed that high expression of these enzymes was associated with poor oxaliplatin-based chemotherapy outcomes in patients. Furthermore, genetic or pharmacological inhibition of CPT2 with perhexiline disturbed NADPH and redox homeostasis and increased reactive oxygen species (ROS) generation and cell apoptosis in gastrointestinal cancer cells following oxaliplatin treatment. Specifically, the combination of oxaliplatin and perhexiline significantly suppressed the progression of gastrointestinal cancer in cell-based xenograft and patient-derived xenograft (PDX) models. Mechanistically, CPT2 was transcriptionally upregulated by nuclear factor of activated T cells 3 (NFATc3), which translocated to the nucleus in response to oxaliplatin treatment. In summary, our study suggests that the inhibition of CPT-mediated FA catabolism combined with conventional chemotherapy is a promising therapeutic strategy for patients with gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Nafamostat mesilate is an anti-inflammatory drug that is usually used to treat pancreatitis. Recent studies show that it can suppress pancreatic cancer via inhibition of the nuclear factor κB (NF-κB) pathway. However, whether it has anti-tumor activity in some other cancer, including colorectal cancer (CRC), has not been investigated and remained unclear. Here, our study showed that nafamostat mesilate abrogated the constitutive NF-κB activation in CRC cells, which is mediated through inhibition of phosphorylation of IκBα and nuclear translocation of p65. Also, we found that nafamostat mesilate inhibited phosphorylation of Erk in CRC cells. Consistently, our study demonstrated that nafamostat mesilate inhibited the CRC cell proliferation, invasion and migration and induced mitochondria-dependent apoptosis. Furthermore, nafamostat mesilate could reverse oxaliplatin induced NF-κB and Erk activation in CRC cells, and enhance the sensitivity of CRC cells to oxaliplatin. Nafamostat mesilate combined with oxaliplatin repressed subcutaneous tumor growth and hepatic metastasis in vivo. Overall, our data suggest that nafamostat mesilate, a relatively non-toxic drug that targets NF-κB and Erk, may, in combination with oxaliplatin, represent a novel therapeutic strategy for CRC treatment. [ABSTRACT FROM AUTHOR]