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Macroautophagy/autophagy acts as an anti-tumor mechanism in early cancer stages but promotes growth in established tumors. Similarly, miRNAs function as tumor suppressors or oncogenes, depending on their target genes. This reciprocal relationship between autophagy and miRNAs is a well-studied area, primarily focused on how miRNAs regulate autophagy-related genes. Our research provides innovative insights into how autophagy selectively controls miRNAs. For instance, MIR224 is preferentially degraded within autophagosomes, leading to the upregulation of SMAD4 and suppressing hepatocellular carcinoma (HCC) tumorigenesis. Conversely, autophagy positively regulates MIR449A by degrading EP300/p300 to activate FOXO1 and facilitate MIR449A transcription in colorectal cancer (CRC). In conclusion, our findings reveal the role of autophagy in maintaining the cellular balance of two miRNAs to mitigate tumorigenic stresses and highlight that autophagy-regulated miRNA profiles may serve as diagnostic and therapeutic markers for cancer development. [ABSTRACT FROM AUTHOR]

Men demonstrate higher incidence and mortality rates of colorectal cancer (CRC) than women. This study aims to explain the potential causes of such sexual dimorphism in CRC from the perspective of sex‐biased gut microbiota and metabolites. The results show that sexual dimorphism in colorectal tumorigenesis is observed in both ApcMin/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)‐treated mice with male mice have significantly larger and more tumors, accompanied by more impaired gut barrier function. Moreover, pseudo‐germ mice receiving fecal samples from male mice or patients show more severe intestinal barrier damage and higher level of inflammation. A significant change in gut microbiota composition is found with increased pathogenic bacteria Akkermansia muciniphila and deplets probiotic Parabacteroides goldsteinii in both male mice and pseudo‐germ mice receiving fecal sample from male mice. Sex‐biased gut metabolites in pseudo‐germ mice receiving fecal sample from CRC patients or CRC mice contribute to sex dimorphism in CRC tumorigenesis through glycerophospholipids metabolism pathway. Sexual dimorphism in tumorigenesis of CRC mouse models. In conclusion, the sex‐biased gut microbiome and metabolites contribute to sexual dimorphism in CRC. Modulating sex‐biased gut microbiota and metabolites could be a potential sex‐targeting therapeutic strategy of CRC. [ABSTRACT FROM AUTHOR]

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]