Up-regulation of PUM1 by miR-218-5p promotes colorectal tumor-initiating cell properties and tumorigenesis by regulating the PI3K/AKT axis

Journal of Gastrointestinal Oncology

article

Qi-Zhi Liu¹  Hai-Rong Yu²  Li-Ping Wang³  Min-Jun Zhou¹  Zhuo Chen¹  De-Hua Zhou¹  Jun-Yi Chen¹  Nan Zhang¹  Zhen-Xing Huang¹  Yu-Xiang Xie¹  Fang-Fang Gu⁴  Kun Li⁵  Xiao-Huang Tu¹ 

[1] Department of Gastrointestinal Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University;Department of Traditional Chinese Medicine, First Clinical Medical College, Heilongjiang University of Traditional Chinese Medicine;Department of Breast Surgery/Plastic Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine;Department of Oncology, Tongren Hospital, Shanghai Jiaotong University School of Medicine;Medicine School, Dalian University

关键词: Pumilio homologous protein 1 (PUM1);    colorectal cancer (CRC);    tumor-initiating cells (T-ICs);    cetuximab;    biomarker;   

DOI  :  10.21037/jgo-23-6

学科分类：肿瘤学

来源: Pioneer Bioscience Publishing Company

【 摘 要 】

Background: Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Advanced stage CRC, during the recent past, had a dismal prognosis and only a few available treatments. Pumilio homologous protein 1 (PUM1) is reportedly aberrant in human malignancies, including CRC. However, the role of PUM1 in the regulation of tumor-initiating cells (T-ICs) remains unknown. Methods: The levels of messenger RNAs (mRNAs) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunoblot analyses. Statistical analyses were performed to determine the associations between the levels of PUM1 and tumor features and patient outcomes. Whether PUM1 is a downstream target of miR-218-5p was verified by bioinformatics target gene prediction and qRT-PCR. Results: Herein, it was found that T-ICs, chemoresistance, and recurrent CRC samples all manifest increased PUM1 expression. Functional investigations have shown that PUM1 increased the self-renewal, tumorigenicity, malignant proliferation, and chemoresistance of colorectal cells. PUM1 activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway biochemically. Furthermore, it was discovered that miR-218-5p specifically targets T-ICs’ PUM1 3'-untranslated region (3'-UTR). More importantly, the PUM1/PI3K/AKT axis regulates CRC cells’ responses to treatment with cetuximab, and PUM1 overexpression increased cetuximab resistance. More evidence points to the possibility that low PUM1 may predict cetuximab benefits in CRC patients after analysis of the patient cohort, patient-derived tumor organoids, and patient-derived xenografts (PDXs). Conclusions: Taken together, the result of this work points to the critical function of the miR-218-5p/PUM1/PI3K/AKT regulatory circuit in regulating T-ICs characteristics and thus suggests possible therapeutic targets for CRC.

【 授权许可】

Unknown