LSM12 facilitates the progression of colorectal cancer by activating the WNT/CTNNB1 signaling pathway

Aberrant activation of the WNT signaling pathway is a joint event in colorectal cancer(CRC),but the molecular mechanism is still unclear.Recently,RNA-splicing factor LSM12(like-Sm protein 12)is highly expressed in CRC tissues.This study aimed to verify whether LSM12 is involved in regulating CRC progression via regulating the WNT signaling pathway.Here,we found that LSM12 is highly expressed in CRC patient-derived tissues and cells.LSM12 is involved in the proliferation,invasion,and apoptosis of CRC cells,similar to the function of WNT signaling in CRC.Furthermore,protein interaction simulation and biochemical experiments proved that LSM12 directly binds to CTNNB1(also known asβ-Catenin)and regulates its protein stability to affect the CTTNB1-LEF1-TCF1 transcriptional complex formation and the associated WNT downstream signaling pathway.LSM12 depletion in CRC cells decreased the in vivo tumor growth through repression of cancer cell growth and acceleration of cancer cell apoptosis.Taken together,we suggest that the high expression of LSM12 is a novel factor leading to aberrant WNT signaling activation,and that strategies targeting this molecular mechanism may contribute to developing a new therapeutic method for CRC.

Omics data analysis reveals the system-level constraint on cellular amino acid composition

Proteins play a pivotal role in coordinating the functions of organisms,essentially governing their traits,as the dynamic arrangement of diverse amino acids leads to a multitude of folded configurations within peptide chains.Despite dynamic changes in amino acid composition of an individual protein(referred to as AAP)and great variance in protein expression levels under different conditions,our study,utilizing transcriptomics data from four model organisms uncovers surprising stability in the overall amino acid composition of the total cellular proteins(referred to as AACell).Although this value may vary between different species,we observed no significant differences among distinct strains of the same species.This indicates that organisms enforce system-level constraints to maintain a consistent AACell,even amid fluctuations in AAP and protein expression.Further exploration of this phenomenon promises insights into the intricate mechanisms orchestrating cellular protein expression and adaptation to varying environmental challenges.

Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma:a single-center,single-arm,phase 2 study

Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal prognosis.Here,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced ICC.Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine(1 g/m2)on Days 1 and 8 and oxaliplatin(85 mg/m2)Q3W for six cycles along with intravenous toripalimab(240 mg)Q3W and oral lenvatinib(8 mg)once daily for one year.The expression of programmed death-ligand 1(PD-L1)and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing(WES)analysis.The primary endpoint was the objective response rate(ORR).Secondary outcomes included safety,overall survival(OS),progression-free survival(PFS),disease control rate(DCR)and duration of response(DoR).As of July 1,2022,the median follow-up time was 23.5 months,and the ORR was 80%.Twenty-three patients achieved partial response,and one achieved complete response.Patients(21/30)with DNA damage response(DDR)-related gene mutations showed a higher ORR,while patients(14/30)with tumor area positivity≥1(PD-L1 staining)showed a trend of high ORR,but without significant difference.The median OS,PFS,and DoR were 22.5,10.2,and 11.0 months,respectively.The DCR was 93.3%.Further,56.7%of patients experienced manageable grade≥3 adverse events(AEs),commonly neutropenia(40.0%)and leukocytopenia(23.3%).In conclusion,toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC.A phase-III,multicenter,double-blinded,randomized study to validate our findings was approved by the National Medical Products Administration(NMPA,No.2021LP01825).

PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma(PDAC),and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

High expression of PD-L1 marks the poor prognosis of pancreatic ductal adenocarcinomas(PDAC).However,the regulatory mechanism of PD-L1 remains elusive.We recently reported that cancer Forkhead box protein 3(Cancer-FOXP3 or C-FOXP3)promoted immune evasion of PDAC by recruiting Treg cells into PDAC via upregulation of CCL5.In this study,we confirmed that PD-L1 was overexpressed in PDAC samples from two independent cohorts of patients with radical resection.Moreover,C-FOXP3 was colocalized and correlated with the expression of PD-L1 in tumor cells at the mRNA and protein levels,and this finding was confirmed by the The Cancer Genome Atlas(TCGA)database.Chromatin immunoprecipitation(ChIP)revealed that C-FOXP3 directly bound to the promoter region of PD-L1 in pancreatic cancer cells.Furthermore,overexpression of C-FOXP3 activated the luciferase reporter gene under the control of the PD-L1 promoter.However,mutation of the binding motif-a completely reversed the luciferase activity.In addition,C-FOXP3-induced upregulation of PD-L1 effectively inhibited the activity of CD8+T cells.Based on our recent finding that the CCL-5 antibody achieved a better response to PDAC models with high C-FOXP3 levels,we further demonstrated that the PD-L1 antibody strengthened the antitumor effect of CCL-5 blockade in xenograft and orthotopic mouse models with high C-FOXP3 levels.In conclusion,C-FOXP3 directly activates PD-L1 and represents a core transcription factor that mediates the immune escape of PDAC.Combined blockade of PD-L1 and CCL-5 may provide an effective therapy for patients with PDAC that have high C-FOXP3 levels.