BACKGROUND: The early diagnosis of gastric cancer (GC) and overcoming chemotherapy resistance is challenging. The aberrant expression of zinc finger protein 281 (ZNF281) and the over-activation of the Wnt/β-catenin pathway are oncogenic factors and confer tumor chemoresistance. ZNF281 modulates the Wnt/β-catenin pathway to influence malignant tumor behavior. However, the role of ZNF281 in GC chemotherapy and the relationship with the Wnt/β-catenin pathway have not been elucidated by researchers.
METHODS: We explored differences in ZNF281 expression in Pan-cancer and normal tissues, the effect of its expression on prognosis of patients treated with 5-fluorouracil (5-FU). Cox regression was utilized to determine whether ZNF281 is an independent prognostic factor. Enrichment analysis was performed to explore the mechanism underlying ZNF281\'s role in 5-FU treatment. We assessed the relationship between ZNF281 and the tumour microenvironment (TME) and combined bulk-RNA and single-cell RNA data to analyse the relationship between ZNF281 and immune infiltration. In vitro experiments verified the effects of ZNF281 knockdown on proliferation, invasion, migration, apoptosis, DNA damage of GC cells with 5-FU treated and the Wnt/β-catenin pathway proteins.
RESULTS: ZNF281 was highly expressed in seven cancers and correlates with the prognosis. It is an independent prognostic factor in 5-FU treatment. ZNF281 correlates with TME score, CD8T cell abundance. ZNF281 is primarily associated with DNA repair and the Wnt/β-catenin pathway. ZNF281 knockdown enhanced the effect of 5-FU on phenotypes of GC cells.
CONCLUSIONS: We identified and verified ZNF281 as one of the potential influencing factors of 5-FU treatment in GC and may be associated with the Wnt/β-catenin pathway. Low ZNF281 may contribute to improved 5-FU sensitivity in GC patients.

The treatment of Colorectal cancer (CRC) is extremely complex and survival rates vary depending on the stage of the disease at the time of diagnosis. Neoadjuvant chemoradiotherapy (NACRT), is the conventional treatment for locally advanced rectal cancer (LARC); however, the resistance to chemoradiotherapy in LARC is difficult to predict.
In this study, clinical data of 126 LARC patients were collected and analyzed, and relevant validation was performed using GEO database and in vitro and in vivo experiments, including Western blotting and Real-time quantitative PCR, immunohistochemistry, immunofluorescence, clonogenic cell survival assays, and nude-mouse xenograft models.
In patients with LARC who were treated with neoadjuvant radiotherapy (NART), higher ZNF281 expression in malignant tissue was associated with a poorer prognosis and lesser degree of tumor regression. Cell and mouse experiments have shown that ZNF281 reduces the damage caused by X-rays to CRC cells and tumors grown in mice.
We found that the expression of ZNF281 predicted the radiation response of CRC cells and suggested the prognosis of patients with LARC who received neoadjuvant radiation therapy.

Regeneration and tumorigenesis are indicated as related processes, while regeneration leads to life and the outcome of tumorigenesis is death. Here, we show the upregulation of zfp281 (zinc finger 281) in our adipose de novo regeneration model through RNA-seq analysis. Then, we validated the upregulation of zfp281 in adipose regeneration via immunofluorescence. Following that, we found that ZNF281 (the human homolog of Zfp281) was upregulated in most types of cancer and related to worse prognosis in 10 tumors. We further investigated the role of ZNF281 in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), pancreatic adenocarcinoma (PAAD), and stomach adenocarcinoma (STAD) and confirmed the high accuracy in the clinical diagnostic feature. Beyond that, based on these three types of cancers, we analyzed the ZNF281-related tumor immune infiltration and DNA methylation sites and finally built risk prediction models for future disease diagnosis. Taken together, our findings provide new insights into the dual role of ZNF281, and we found that it was a potential biomarker for regeneration and tumor prognosis.

Crohn\'s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis.

As one of the most aggressive malignancies, non-small cell lung carcinoma (NSCLC) has high risks of death. It has been demonstrated that circRNAs accelerate NSCLC progression, but the underlying molecular mechanisms of circRNAs in NSCLC were still obscure. In the first place, the circRNA microarray of NSCLC was investigated in this study, and hsa_circ_0008003 (circ-0008003) was chosen as the research object. Then, it was unveiled that the expression of circ-0008003 examined via qRT-PCR was elevated in tumour tissues relative to the non-tumour tissues, which was associated with TNM stage and lymphatic metastasis in NSCLC. Additionally, the prognosis of NSCLC patients with high circ-0008003 level was poor. Besides, circ-0008003 silencing dampened the invasion and proliferation of NSCLC cells. Next, according to the mechanistic studies, circ-0008003 functioned as a ceRNA of ZNF281 in NSCLC by acting as the endogenous sponge for miR-488, which was proved to be a tumour suppressor in NSCLC. Additionally, ZNF281 overexpression and miR-488 suppression recovered the influences of repressed circ-0008003 on NSCLC cellular processes. It was validated in this research that circ-0008003 triggered tumour formation in NSCLC, which was adjusted via miR-488/ZNF281 axis, casting a novel light on the resultful target for treating NSCLC and predicting the prognosis.

UNASSIGNED: The chemoresistance of 5-fluorouracil (5-FU) limited the application of chemotherapy in colorectal cancer (CRC) treatment. Herein, we aimed to uncover the potential mechanism behind the 5-FU resistance of CRC cells.
UNASSIGNED: The abundance of long noncoding RNA urothelial carcinoma associated 1 (lncRNA UCA1), microRNA-23b-3p (miR-23b-3p) and zinc finger protein 281 (ZNF281) was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in CRC tissues and cells. Western blot was conducted to examine autophagy-related proteins, apoptosis-associated proteins and ZNF281 in CRC tissues and cells. Cell counting kit-8 (CCK8) assay was performed to detect the viability and inhibitory concentration 50% (IC50) value of 5-FU of CRC cells. The apoptosis of CRC cells was measured by flow cytometry. The binding sites between miR-23b-3p and UCA1 or ZNF281 were predicted by miRcode and Starbase software, respectively, and the combination was confirmed by dual-luciferase reporter assay and RIP assay. Murine xenograft model was established to verify the role of UCA1 on the 5-FU resistance of CRC in vivo.
UNASSIGNED: The 5-FU resistance of CRC was positively related to the level of UCA1 and autophagy. UCA1 accelerated the 5-FU resistance of CRC cells through facilitating autophagy and suppressing apoptosis. MiR-23b-3p was a target of UCA1 in 293T and CRC cells. The knockdown of miR-23b-3p reversed the inhibitory effects of UCA1 interference on the 5-FU resistance and autophagy and the promoting impact on the apoptosis of CRC cells. ZNF281 could bind to miR-23b-3p in 293T cells. MiR-23b-3p elevated the 5-FU sensitivity through down-regulating ZNF281 in CRC cells. UCA1 interference enhanced the 5-FU sensitivity of CRC through miR-23b-3p/ZNF281 axis in vivo.
UNASSIGNED: UCA1 mediated 5-FU resistance of CRC cells through facilitating autophagy and inhibiting apoptosis via miR-23b-3p/ZNF281 axis in vivo and in vitro.

A recent study reported that zinc finger protein (ZNF)281 is a tumor-suppressive long non-coding (lnc)RNA in glioma. The present study investigated the role of ZNF281 in non-small cell lung cancer (NSCLC). ZNF281 expression in paired cancer and non-cancerous tissues from patients with NSCLCs was analyzed by RNA extraction and reverse transcription-quantitative-PCR. A 5-year follow up on patients was performed to analyze the prognostic value of ZNF281 for NSCLC. Cell transfections of ZNF281 or phosphatase and tensin homolog (PTEN) expression vector and microRNA (miR)-221 mimic were performed to analyze the relationship between ZNF281, miR-221 and PTEN. Cell apoptosis and proliferation were analyzed using Cell Counting Kit-8 and flow cytometry, respectively. In patients with NSCLC, expression levels of ZNF281 were significantly lower in cancer tissues compared with in non-cancerous tissues, and lower levels of ZNF281 expression in cancerous tissues predicted poor survival. In NSCLC cells, ZNF281 overexpression resulted in upregulated PTEN and downregulated miR-221 expression, whereas cells with miR-221 overexpression exhibited downregulated PTEN expression and unaffected ZNF281 expression. In addition, ZNF281 and PTEN overexpression resulted in accelerated cell apoptosis and inhibited the cell proliferation of NSCLC cells. Notably, miR-221 overexpression exhibited an opposite effect and attenuated the functions of ZNF281 and PTEN overexpression. Therefore, ZNF281 may upregulate PTEN via downregulation of miR-221 in NSCLC, resulting in inhibition of cancer cell proliferation and the promotion of apoptosis.

Breast cancer is the most common malignancy, and metastasis is the main cause of cancer-associated mortality in women worldwide. Transforming growth factor-β (TGF-β) signaling, an inducer of epithelial-to-mesenchymal transition (EMT), plays an important role in breast cancer metastasis. Abnormal expression of miR-543 is associated with tumorigenesis and progression of various human cancers; however, the knowledge about the role of miR-543 in breast cancer metastasis is still unknown. In this study, we demonstrated that miR-543 inhibits the EMT-like phenotype and TGF-β-induced breast cancer metastasis both in vitro and in vivo by targeting ZNF281. ZNF281 transactivates the EMT-related transcription factor ZEB1 and Snail. Furthermore, both ZEB1 and Snail can transcriptionally suppress miR-543 expression. Taken together, our data uncover the ZNF281-miR-543 feedback loop and provide a mechanism to extend the understanding of TGF-β network complexity.

It has previously been determined that long non-coding (lnc)RNA-zinc finger protein (ZNF)281 serves an oncogenic role in breast cancer; however, the role of lncRNA-ZNF281 in other cancer types is yet to be elucidated. The present study aimed to analyze the role of ZNF281 in gastric cancer by characterizing its activity in cancerous tissues and normal tissues using RT-qPCR. Overexpression experiments were also performed to investigate the interaction between ZNF281 and miR-124, and Transwell assays were conducted to analyze cell invasion and migration. The present study revealed that lncRNA-ZNF281 was upregulated, and that microRNA (miR)-124 was downregulated, in cancerous tissues compared with that in the paired adjacent healthy tissues of patients with gastric cancer. In addition, the expression levels of lncRNA-ZNF281 and miR-124 exhibited a significant inverse association. Furthermore, in vitro cell experiments determined that lncRNA-ZNF281 overexpression resulted in miR-124 inhibition, yet miR-124 overexpression did not influence lncRNA-ZNF281 expression. lncRNA-ZNF281 expression level was also associated with the clinical stage of the patient. Bioinformatics analysis revealed that lncRNA-ZNF281 may target the base pairs in the hairpin loop of the miR-124 precursor. Subsequent in vitro cell experiments indicated that lncRNA-ZNF281 overexpression resulted in promoting the migration and invasiveness of gastric cancer cells, while miR-124 over-expression led to its inhibition. In addition, miR-124 overexpression partially recovered the effects of lncRNA-ZNF281 overexpression. Therefore, lncRNA-ZNF281 may promote cancer cell migration and invasion in gastric cancer via downregulation of miR-124.

Background: LncRNA-ZNF281 suppresses glioma, whereas its role in hepatocellular carcinoma (HCC) is unclear. This study aimed to investigate the interaction between ZNF281 and miR-539 in HCC. Materials and Methods: This study included 66 HCC patients (40 men and 26 women; 36-68 years, 53.1 ± 6.2 years) who were selected from the 133 HCC cases admitted to The First Affiliated Hospital of Fujian Medical University from February 2011 to June 2014. Levels of ZNF281 and miR-539 expression in two types of tissues (HCC and nontumor) were measured by performing quantitative polymerase chain reaction (qPCR). Dual-luciferase assay was performed to analyze the interactions between miR-539 and ZNF281 in both SNU-475 and PLHC-1 cells. The effects of ZNF281 and miR-539 overexpression on the invasion and migration of HCC cells were analyzed by performing transwell assays. Results: The authors showed that ZNF281 was upregulated and miR-539 was downregulated in HCC tissues and were negatively correlated. High levels of ZNF281 and low levels of miR-539 predicted the poor survival of HCC patients. Overexpression analysis showed that ZNF281 and miR-539 overexpression led to the downregulation of each other. Transwell assays showed that ZNF281 overexpression led to enhanced and miR-539 overexpression led to suppressed HCC cell invasion and migration. In addition, miR-539 overexpression attenuated the effects of ZNF281 overexpression. Conclusions: Therefore, ZNF281 may interact with miR-539 to promote HCC cell invasion and migration.