A novel TP53 pathway influences the HGS-mediated exosome formation in colorectal cancer.
Tumor-derived exosomes are important for cell-cell communication. However, the role of TP53 in the control of exosome production in colorectal cancer (CRC) is controversial and unclear. The features of exosomes secreted from HCT116 TP53-wild type (WT), TP53-knockout (KO) and constructed TP53 (R273H)-mutant (MT) cells were assessed. The exosomes from the MT and KO cells exhibited significantly reduced sizes compared with the WT cells. A comprehensive proteomic analysis of exosomal proteins was performed using the isobaric tag for relative and absolute quantitation (iTRAQ)-2D-LC-MS/MS strategy. A total of 3437 protein groups with ≥2 matched peptides were identified. Specifically, hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) was consistently down-regulated in the exosomes from the MT and KO cells. Functional studies demonstrated that low HGS levels were responsible for the decreased exosome size. TP53 regulated HGS expression and thus HGS-dependent exosome formation. Furthermore, the HGS expression was gradually increased concomitant with CRC carcinogenesis and was an independent poor prognostic factor. In conclusion, a novel HGS-dependent TP53 mechanism in exosome formation was identified in CRC. HGS may serve as a novel prognostic biomarker and a candidate target for therapeutic interventions.
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Yulin
Y
Sun
Center of Basic Medical Science, Navy General Hospital, Beijing 100048, China.
Weiwei
W
Zheng
Core Facility of Instruments, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, China.
Zhengguang
Z
Guo
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Qiang
Q
Ju
Department of Clinical Biochemistry, Chinese PLA General Hospital, Beijing 100853, China.
Lin
L
Zhu
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Jiajia
J
Gao
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Lanping
L
Zhou
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Fang
F
Liu
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Yang
Y
Xu
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Qimin
Q
Zhan
Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Zhixiang
Z
Zhou
Core Facility of Instruments, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, China.
Wei
W
Sun
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, China.
Xiaohang
X
Zhao
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D020543:Proteome / Q000032:analysis; D040901:Proteomics; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D020543:Proteome; D016159:Tumor Suppressor Protein p53; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate