Abstract
HMGB1-RAGE signaling plays an integral role in inflammation-driven carcinogenesis. In the present study, we showed that RAGE has direct association with K-Ras following HMGB1 exposure in colorectal cancer (CRC) cells. Immunofluorescence analysis revealed a significant co-localization between RAGE and K-Ras in HMGB1-exposed CRC cells. Moreover, we uncovered that HMGB1-mediated RAGE activation led to Yap1 accumulation in a Ras-dependent mechanism in CRC cells. HMGB1 activated the expression of Yap1 downstream stemness marker proteins CD44 and Sox2 in RAGE- and Ras-dependent manners. Furthermore, HMGB1 exposure led to the proliferation of CRC cells and the expansion of CRC stem cells. RAGE, Yap1 and CD44 were overexpressed in CRC specimens. Linear regression analysis revealed that the expression of RAGE was positively correlated with Yap1 in clinical CRC specimens. Both of RAGE and Yap1 expression were correlated with advanced histological grades, lymph node metastasis and TNM stages. Finally, we revealed that both of RAGE and Yap1 expression could predicted unfavorable prognosis in CRC patients. These findings implicated that HMGB1-RAGE signaling may promote Yap1 activation and CRC progression, shedding new light on the mechanisms underlying inflammation-driven CRC development.
Keywords:
HMGB1; K-Ras; RAGE; Yap1; colorectal cancer; stemness.
© 2018 Wiley Periodicals, Inc.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / metabolism*
-
Adenocarcinoma / genetics
-
Adenocarcinoma / metabolism
-
Adenocarcinoma / secondary*
-
Antigens, Neoplasm / genetics
-
Antigens, Neoplasm / metabolism*
-
Apoptosis
-
Biomarkers, Tumor / genetics
-
Biomarkers, Tumor / metabolism
-
Cell Proliferation
-
Colorectal Neoplasms / genetics
-
Colorectal Neoplasms / metabolism
-
Colorectal Neoplasms / pathology*
-
Female
-
Follow-Up Studies
-
Gene Expression Regulation, Neoplastic
-
HMGB1 Protein / genetics
-
HMGB1 Protein / metabolism*
-
Humans
-
Male
-
Middle Aged
-
Mitogen-Activated Protein Kinases / genetics
-
Mitogen-Activated Protein Kinases / metabolism*
-
Neoplasm Invasiveness
-
Neoplasm Metastasis
-
Neoplastic Stem Cells / metabolism
-
Neoplastic Stem Cells / pathology*
-
Phosphoproteins / genetics
-
Phosphoproteins / metabolism*
-
Prognosis
-
Proto-Oncogene Proteins p21(ras) / genetics
-
Proto-Oncogene Proteins p21(ras) / metabolism*
-
Survival Rate
-
Transcription Factors
-
Tumor Cells, Cultured
-
YAP-Signaling Proteins
Substances
-
Adaptor Proteins, Signal Transducing
-
Antigens, Neoplasm
-
Biomarkers, Tumor
-
HMGB1 Protein
-
HMGB1 protein, human
-
KRAS protein, human
-
Phosphoproteins
-
Transcription Factors
-
YAP-Signaling Proteins
-
YAP1 protein, human
-
MOK protein, human
-
Mitogen-Activated Protein Kinases
-
Proto-Oncogene Proteins p21(ras)