HMGB1‐RAGE signaling facilitates Ras‐dependent Yap1 expression to drive colorectal cancer stemness and development

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 RAGEand 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 inflammationdriven CRC development. K E Y W O R D S colorectal cancer, HMGB1, K-Ras, RAGE, stemness, Yap1

Adenovirus infection promotes the formation of glioma stem cells from glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

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Prognostic and clinicopathological significance of YAP in Colorectal carcinoma: A systematic review and meta-analysis

“…We excluded 941 articles after screening the titles and abstracts. Then we included 12 studies after reviewing 43 Full-text articles in detail [9][10][11][12][13][14][15][16][17][18][19][20]. A owchart of the retrieval process is shown in Fig.1.…”

Adenovirus infection promotes the formation of glioma stem cells by glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

“…TLR9 could be triggered by a panel of DAMPs such as CpG-containing oligodeoxyribonucleotides (CpG-ODN) and HMGB1, with the later enriched in TME as an alarmin of tissue injury [24][25][26]51 . We then tested the effects of these two TLR9 agonists on primary glioma cells.…”

“…For example, hypoxia, which is a fundamental characteristic of TME in solid tumors, promotes the formation and inhibits the differentiation of CSCs in many tumor models 20, 21 .Inflammation, which is another hallmark of cancer, generates a large array of cytokines that promote stemness of cancer cells 22,23 . Moreover, some of the damage-associated molecular patterns (DAMPs) such as the high mobility group box 1 (HMGB1) derived from tumor cells or TME could also promote the CSC phenotype via innate immune signaling [24][25][26] . Mechanistically, toll-like receptor 9 (TLR9)/myeloid differentiation primary response gene 88 (MYD88) pathway 27-29 , signal transducer and activator of transcription 3 (STAT3) 30 , as well as some long non-coding RNA such as the nuclear enriched abundant transcript 1 (NEAT1) 31-34 , have been implicated.…”