Cancer Cell: Breakthrough! Li Lin/Wu Tianqing/Li Wei collaborated to discover a new strategy for treating muscosa in the treatment room

Li Lin of the Center for Excellence and Innovation in Molecular Cell Science of the Chinese Academy of Sciences (Institute of Biochemistry and Cell Biology), Wu Tianqing of Yale University, and Li Wei of Fudan University Children's Hospital, worked together to publish a research paper entitled: Elevated CXorf67 Expression in PFA Epymomas Suppresses DNA Repair and Sensitizes to PARP Addors.
The study first found that CXorf67 protein could be used as an important biomarker for the use of PARP inhibitors for intracranial PFA-type chamber membrane tumors in children, and found that combined radiotherapy of PARP inhibitors is an effective means of treating intracranial PFA-type cerial tube meningioma in children.
-room muscular melanoma (Ependymoma) is a common brain tumor in children, which occurs in the posterior cranial den, wherein the incidence and malignancy of the PFA (posterior fossa group A, cranial nest class A) subtype is the highest, mainly in children with an average age of 3 years, about 40% incurable.
room tube melanoma is currently operated on and radiotherapy as the main treatment, but the lack of effective chemotherapy drugs, especially in infants under three years of age, because of the inability to accept radiation, the overall prognosis after surgery is poor, so the search for effective targeted drugs has become a difficult problem in the neurosurgery community to treat this type of tumor.
team, while studying Wnt signal-regulated DNA damage repair, identified CXorf67 as possible to be involved in DNA damage repair through phosphorylation mass spectrometry.
CXorf67 gene is located at Xp11.22 on the chromosome, with only one exon encoding 503 amino acids.
CXorf67 is not expressed or expressed very low in the vast majority of cells and tissues, but there have been reports of high expression of CXorf67 in PFA subtypes of cergioma.
2019, it was reported that CXorf67 could be involved in regulating histoprotein methylation (H3K27me3) levels, but whether CXorf67 was involved in DNA damage repair and its molecular mechanisms has not been studied.
researchers first found through bioinflogic analysis that CXorf67 highly expressed cells are more sensitive to DNA damage reagents, and further through immuno-precipitation-mass spectrometry analysis, found that CXorf67 may bind proteins containing a range of proteins associated with DNA damage repair.
then, the researchers confirmed that CXorf67 could indeed respond to DNA damage signals and be rich in chromosomes, and by comparing CXorf67 wild and gene knock-out cell line, they found that CXorf67 inhibited the DNA damage repair process.
, using a reported gene system of DNA injury repair pathways, the researchers found that CXorf67 inhibited the DNA damage repair process primarily by regulating the same-origin recombination repair pathway.
further mechanism studies have found that CXorf67 inhibits the participation of the BRCA2-PALB2 complex in the mediated iso-recombination repair by competing with the BRCA2 protein to bind the PALB2 protein.
Poly-ribose (ADP-ribose) polymerase (PARP) is a protease that plays an important role in basic life activities such as DNA repair and cell differentiation and death, and has been a high-profile target for cancer treatment in biology and medicine in recent years.
PARP inhibitors block DNA single-stranded fracture repair, DNA replication produces double-stranded, if there is a defect in the TUMOR cell's DNA dual-stranded combination repair, then the cell can not carry out DNA repair, and thus death;
, targeted PARP inhibitors have been approved for clinical treatment of tumors with iso-recombinant defects such as breast and ovarian cancer.
CXorf67 inhibits DNA isomorly recombinant repair, so theoretically CXorf67 highly expressed tumor cells may be sensitive to PARP inhibitors.
to confirm this,
researchers first verified that the high expression of CXorf67 significantly increased cell sensitivity to PARP inhibitors by comparing CXorf67 wild and knock-out cells, as well as by complementing CXorf67 in knock-out cells.
, the researchers established a model of primary cell line and human-source tumor xenon transplantation in patients with cerpenus melanoma, and the results also confirmed that the highly expressed tumors of CXorf67 were more sensitive to PARP inhibitors.
addition, CXorf67 enhances the tumor's lethal effect on tumors more significantly when used in union with radiotherapy.
these studies consistently show that CXorf67 can be used as a biomarker to guide the targeted treatment of PFA-type tracheal membrane tumors.
CXorf67 as an important biomarker that can be used to guide the targeted treatment of PFA tumors.
CXorf67 low-expression or non-expressive PFA-type chamber membrane tumor, homogen recombination repair is carried out normally, tumor cell survival (left), while in CXorf67 high expression PFA-type chamber membrane tumor, homolytic recombination repair pathway is inhibited, when treated with PARP inhibitor drugs, tumor cells are killed (right).
Researcher Li Lin of the Center of Molecular Cell Excellence of the Chinese Academy of Sciences, Professor Wu Tianqing of Yale University and Director li Wei of Fudan University Children's Hospital are co-authors of this article, and Ph.D. students Han Zhichang, Yu Meng, Bai Yixuan and Fudan Children's Hospital Yu Jianzhong are co-authors.
the research was supported by Zeng Wei Researcher, Cell Analysis Technology Platform, Animal Experimental Technology Platform, etc. of the Center of Molecular Cell Excellence.