Chemotherapy represents an important treatment option for colorectal cancer (CRC), but only half of the patients benefit from these regimens. We explored the potential predicting value and mechanism of PIK3CA mutation in CRC chemotherapy. CRC specimens from 440 patients were retrospectively collected and examined with a fluorescence PCR-based method. The correlation of first-line chemotherapy response and PIK3CA mutation was evaluated according to follow-up and medical records. The underlying mechanism of PIK3CA mutation in chemotherapy resistance was assessed with CRC tumors and primary cells. The mutation frequency of the PIK3CA gene in CRC patients was 9.55%, which was correlated with late TNM staging and lower histological grade. The CRC patients with PIK3A mutation showed worse response to first-line chemotherapy than those without PIK3CA mutation. PIK3A mutation tumor cells showed poor sensitivity to first-line chemotherapy in vitro and in vivo. PIK3CA mutation induced PI3K/Akt signaling activation to increase LGR5+ CRC stem cells survival and proliferation, from which lead to chemotherapy resistance. Furthermore, PIK3CA mutation/LGR5+ expression was an independent detrimental factor for CRC patients. Our findings indicated that PIK3CA mutation induced PI3K/Akt activation contributed to CRC stem cells survival and proliferation, from which cells further resistance to chemotherapy. PIK3CA mutation/LGR5+ expression was a potential biomarker for monitoring chemotherapy resistance in CRC.

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Background Although a substantial increase in the survival of patients with other cancers has been observed in recent decades, pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases. No effective screening approach exists. Methods Differential exosomal long noncoding RNAs (lncRNAs) isolated from the serum of patients with PDAC and healthy individuals were profiled to screen for potential markers in liquid biopsies. The functions of LINC00623 in PDAC cell proliferation, migration and invasion were confirmed through in vivo and in vitro assays. RNA pulldown, RNA immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays and rescue experiments were performed to explore the molecular mechanisms of the LINC00623/NAT10 signaling axis in PDAC progression. Results A novel lncRNA, LINC00623, was identified, and its diagnostic value was confirmed, as it could discriminate patients with PDAC from patients with benign pancreatic neoplasms and healthy individuals. Moreover, LINC00623 was shown to promote the tumorigenicity and migratory capacity of PDAC cells in vitro and in vivo. Mechanistically, LINC00623 bound to N-acetyltransferase 10 (NAT10) and blocked its ubiquitination-dependent degradation by recruiting the deubiquitinase USP39. As a key regulator of N4-acetylcytidine (ac4C) modification of mRNA, NAT10 was demonstrated to maintain the stability of oncogenic mRNAs and promote their translation efficiency through ac4C modification. Conclusions Our data revealed the role of LINC00623/NAT10 signaling axis in PDAC progression, showing that it is a potential biomarker and therapeutic target for PDAC.