Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1-mediatedMAPK signaling

Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.

A YAP/TAZ-CD54 axis is required for CXCR2-CD44-tumor-specific neutrophils to suppress gastric cancer

As an important part of tumor microenvironment,neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis.Here we defined,at single-cell resolution,CD44-CxCR2-neutrophils as tumor-specific neutrophils(tsNeus)in both mouse and human gastric cancer(GC).We uncovered a Hippo regulon in neutrophils with unique YAP signature genes(e.g.,ICAM1,CD14,EGR1)distinct from those identified in epithelial and/or cancer cells.Importantly,knockout of YAP/TAz in neutrophils impaired their differentiation into CD54+tsNeus and reduced their antitumor activity,leading to accelerated GC progression.Moreover,the relative amounts of CD54+tsNeus were found to be negatively associated with GC progression and positively associated with patient survival.Interestingly,GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+tsNeus.Furthermore,pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC,with no significant inflammation-related side effects.Thus,our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus,opening a new possibility to develop neutrophil-based antitumor therapeutics.

A new membrane anatomy-oriented classification of radical surgery for rectal cancer

For patients with different clinical stages of rectal cancer,tailored surgery is urgently needed.Over the past 10 years,our team has conducted numerous anatomical studies and proposed the“four fasciae and three spaces”theory to guide rectal cancer surgery.Enlightened by the anatomical basis of the radical hysterectomy classification system of Querleu and Morrow,we proposed a new classification system of radical surgery for rectal cancer based on membrane anatomy.This system categorizes the surgery into four types(A–D)and incorporates corresponding subtypes based on the preservation of the autonomic nerve.Our surgical classification unifies the pelvic membrane anatomical terminology,validates the feasibility of classifying rectal cancer surgery using the theory of“four fasciae and three spaces,”and lays the theoretical groundwork for the future development of unified and standardized classification of radical pelvic tumor surgery.