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

Abstract

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.

Effect of microRNA-515-5p on Biological Behavior of Colorectal Cancer Cells through Phosphoinositide 3-Kinase/ Protein Kinase B Signaling Pathway

“…In recent years, miRNA has emerged as a prominent area of research within the field of malignant tumors. As a group of non-coding siRNA, it CRC is a prevalent malignancy affecting the digestive system, specifically the colon or rectum, with high morbidity and mortality [6] . The prevalence of CRC is progressively increasing in our country due to the exacerbation of the aging issue and the alteration of individual's lifestyle patterns.…”

WTAP‐induced N6‐methyladenosine of PD‐L1 blocked T‐cell‐mediated antitumor activity under hypoxia in colorectal cancer

“… 1 Colorectal cancer (CRC) is the third most prevalent form of malignant tumor and the leading cause of cancer‐related mortalities worldwide. 2 Colorectal cancers have hypoxic areas, as in several other solid tumors. 3 Several inhibitors that target hypoxic tumor cells have been developed because growing amounts of data have shown that numerous factors, such as hypoxia‐inducible factor 1 alpha (HIF‐1α), are crucial for the survival, angiogenesis, invasion, and invasion and metastasis of hypoxic tumor cells.…”

“…Solid tumors frequently exhibit hypoxia, which enhances the progression and development of many types of cancer 1 . Colorectal cancer (CRC) is the third most prevalent form of malignant tumor and the leading cause of cancer‐related mortalities worldwide 2 . Colorectal cancers have hypoxic areas, as in several other solid tumors 3 .…”