miR‑221 inhibits autophagy and targets TP53INP1 in colorectal cancer cells

Abstract

Abstract. Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated mortalities worldwide. MicroRNAs (miRNAs/miRs) serve important roles in tumor development, progression and metastasis. miR-221 has been reported to modulate proliferation, apoptosis, cell cycle distribution and cell migration in a variety of cancers. However, the function of miR-221 in the autophagy of cancer is unclear. In the present study, the role of miR-221 in the autophagy of CRC cells was investigated and its associated target was identified. Survival analysis using The Cancer Genome Atlas data suggested that a higher expression of miR-221 was associated with poor survival in patients with CRC. A Cell Counting kit-8 assay revealed that miR-221 promoted CRC cell proliferation. Autophagy flux analyzed by microtubule-associated protein 1 light chain 3 (LC3) turnover indicated that miR-221 reduced autophagy in CRC cells using different protease inhibitors (E64d and pepstatin A; Bafilomycin A1) in nutrient-rich medium or under starvation conditions. Tumor protein 53-induced nuclear protein 1 (TP53INP1) was identified as a potential novel target of miR-221 by bioinformative prediction. The protein expression of TP53INP1 was inversely regulated by miR-221 in CRC cells. Furthermore, luciferase activity assays were performed and indicated that miR-221 may regulate the luciferase activity of wild-type TP53INP1 without interfering with the activity of mutant TP53INP1. These data suggested that miR-221 may promote the cell proliferation of CRC via the inhibition of autophagy and targeted TP53INP1. IntroductionColorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-associated death worldwide (1). The morbidity rates of CRC are increasing substantially in a number of countries within Eastern Asia and Eastern Europe which were previously at low risk (2). The multifactorial etiology of CRC involves lifestyle and dietary factors, such as smoking, red and processed meat consumption, and excessive alcohol consumption (3). Autophagy is a vital transformational switch among mechanisms that are involved in the pathogenesis of CRC (4). Autophagy may act as a suppressor during early stages and as a promoter during advanced stages of CRC (4,5). It is important to determine the regulative mechanisms of autophagy in CRC.Recent studies suggests that the post-transcription and translation regulation mediated by microRNAs (miRNAs/miRs) contribute significantly to autophagy in cancer (6). It is found that miR-23b-3p inhibits autophagy in gastric cancer cells (7) and miR-26 suppresses autophagy in hepatocellular carcinoma cells (8). Whereas miR-193b is suggested to induce autophagy in oesophageal cancer cells (9). It is interesting that different miRNAs play diverse roles in the regulation of autophagy through various targets.

Transcriptome Profiling of Bovine Macrophages Infected by Mycobacterium avium spp. paratuberculosis Depicts Foam Cell and Innate Immune Tolerance Phenotypes

“…Table 4). The p53-inducible protein 1 (TP53INP1) promotes autophagy by interacting with autophagosome-localized autophagyrelated protein family (ATG) proteins (49). Even though ATG4D expression was slightly (∼2-fold) sustained by 4 hpi and throughout the infection period, TP53INP1 was repressed by 2.6-fold at 8 hpi ( Supplementary Table 4).…”

lncRNA GAS5 Reverses EMT and Tumor Stem Cell-Mediated Gemcitabine Resistance and Metastasis by Targeting miR-221/SOCS3 in Pancreatic Cancer

“…Dysregulation of miRNAs is involved in many cancers, and some miRNAs function as tumor suppressors or oncogenes. 16 , 17 miR-221 has been identified as an oncogene in many types of cancers, including colorectal cancer, 18 breast cancer, 19 and osteosarcoma. 20 Bioinformatics analysis found that miR-221 was a target of GAS5.…”

LncRNA NR_027471 Functions as a ceRNA for miRNA-8055 Leading to Suppression of Osteosarcoma by Regulating the Expression of TP53INP1

“…By antagonizing TP53INP1 and Yes1 associated transcriptional regulator (YAP1), upregulated miR-200a enhances drug resistance in breast cancer (24). In colorectal cancer, miR-221 promoted cell proliferation via the inhibition of autophagy and targeted TP53INP1 (25). In this study, TP53INP1 was predicted and confirmed to be a target of miR-8055.…”