TY - JOUR
T1 - Loss of HES1 expression is associated with extracellular matrix remodeling and tumor immune suppression in KRAS mutant colon adenocarcinomas
AU - Wang, Lei
AU - Gu, Wenchao
AU - Zou, Bingqing
AU - Kalady, Matthew
AU - Xin, Wei
AU - Zhou, Lan
N1 - Funding Information:
This work was supported in part by research funding from NCI CA222064, NIH HL103827, Case GI SPORE Research Development Award, and NIDDK DDRCC Pilot/Feasibility Award (to LZ), NCI CA193359 (to MK), and by the Department of Pathology Case Western Reserve University faculty startup fund to WX and LZ. SPORE Pilot grants (to LZ).
Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/9/25
Y1 - 2023/9/25
N2 - The loss of HES1, a canonical Notch signaling target, may cooperate with KRAS mutations to remodel the extracellular matrix and to suppress the anti-tumor immune response. While HES1 expression is normal in benign hyperplastic polyps and normal colon tissue, HES1 expression is often lost in sessile serrated adenomas/polyps (SSAs/SSPs) and colorectal cancers (CRCs) such as those right-sided CRCs that commonly harbor BRAF or KRAS mutations. To develop a deeper understanding of interaction between KRAS and HES1 in colorectal carcinogenesis, we selected microsatellite stable (MSS) and KRAS mutant or KRAS wild type CRCs that show aberrant expression of HES1 by immunohistochemistry. By comparing the transcriptional landscapes of microsatellite stable (MSS) CRCs with or without nuclear HES1 expression, we investigated differentially expressed genes and activated pathways. We identified pathways and markers in the extracellular matrix and immune microenvironment that are associated with mutations in KRAS. We found that loss of HES1 expression positively correlated with matrix remodeling and epithelial-mesenchymal transition but negatively correlated with tumor cell proliferation. Furthermore, loss of HES1 expression in KRAS mutant CRCs correlates with a higher M2 macrophage polarization and activation of IL6 and IL10 immunosuppressive signature. Identifying these HES1-related markers may be useful for prognosis stratification and developing treatment for KRAS-mutant CRCs.
AB - The loss of HES1, a canonical Notch signaling target, may cooperate with KRAS mutations to remodel the extracellular matrix and to suppress the anti-tumor immune response. While HES1 expression is normal in benign hyperplastic polyps and normal colon tissue, HES1 expression is often lost in sessile serrated adenomas/polyps (SSAs/SSPs) and colorectal cancers (CRCs) such as those right-sided CRCs that commonly harbor BRAF or KRAS mutations. To develop a deeper understanding of interaction between KRAS and HES1 in colorectal carcinogenesis, we selected microsatellite stable (MSS) and KRAS mutant or KRAS wild type CRCs that show aberrant expression of HES1 by immunohistochemistry. By comparing the transcriptional landscapes of microsatellite stable (MSS) CRCs with or without nuclear HES1 expression, we investigated differentially expressed genes and activated pathways. We identified pathways and markers in the extracellular matrix and immune microenvironment that are associated with mutations in KRAS. We found that loss of HES1 expression positively correlated with matrix remodeling and epithelial-mesenchymal transition but negatively correlated with tumor cell proliferation. Furthermore, loss of HES1 expression in KRAS mutant CRCs correlates with a higher M2 macrophage polarization and activation of IL6 and IL10 immunosuppressive signature. Identifying these HES1-related markers may be useful for prognosis stratification and developing treatment for KRAS-mutant CRCs.
KW - Humans
KW - Colonic Neoplasms/genetics
KW - Proto-Oncogene Proteins p21(ras)/genetics
KW - Adenocarcinoma/genetics
KW - Immunosuppression Therapy
KW - Extracellular Matrix/genetics
KW - Tumor Microenvironment/genetics
KW - Transcription Factor HES-1/genetics
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U2 - 10.1038/s41598-023-42234-7
DO - 10.1038/s41598-023-42234-7
M3 - Article
C2 - 37749297
AN - SCOPUS:85172024604
SN - 2045-2322
VL - 13
SP - 15999
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 15999
ER -