Key Takeaways & Executive Findings
- •• LINC00114 and HNRNPA1 are overexpressed in colorectal cancer and positively correlate with CD31, a marker of angiogenesis. • Silencing LINC00114 inhibits CRC cell proliferation, metastasis, and HNRNPA1 expression, and suppresses HUVEC tubule formation. • LINC00114 binds to HNRNPA1 and regulates glutamine metabolism reprogramming, which is crucial for CRC metastasis. • In vivo, LINC00114 intervention represses tumor progression and vascular normalization, highlighting its potential as a therapeutic target.
Abstract
Colorectal cancer (CRC) is a common type of gastrointestinal malignancy, and it has a close connection with long noncoding RNAs (lncRNAs). This study aims to examine the involvement of long noncoding RNA LINC00114, which targets heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) in regulating glutamine metabolism and angiogenesis in the metastasis of colorectal cancer (CRC). LINC00114 and HNRNPA1 levels are measured in CRC tissues and cells to determine their expression levels. Then, siRNA targeting LINC00114 (si-LINC00114) is used to transfect CRC cells, and cell proliferation and metastasis are detected. The influence of exogenous glucose and glutamine supplementation on angiogenesis induced by LINC00114 in CRC is investigated in HUVECs. Glutamine metabolism in CRC cells is also detected. Furthermore, the role of LINC00114 in CRC xenograft tumors is studied in vivo. LINC00114 and HNRNPA1 are highly expressed in CRC and positively correlate with CD31. si-LINC00114 significantly inhibits proliferation, metastasis and HNRNPA1 expression in CRC cells. An RNA-binding-protein immunoprecipitation (RIP) assay confirms that LINC00114 can bind to HNRNPA1 and positively regulate its expression. Further experiments confirm that si-LINC00114 significantly inhibits cell proliferation and tubule formation in HUVECs. Exogenous glucose and glutamine supplementation significantly promotes the levels of LINC00114 and HNRNPA1 in CRC cells and promotes tubule formation in HUVECs. In addition, transfection of CRC cells with si-LINC00114 and/or oe-HNRNPA1 regulates glutamine metabolism in CRC cells. Animal studies confirm that intervention with LINC00114 represses the progression and vascular normalization of CRC and regulates glutamine metabolism. In conclusion, LINC00114 promotes CRC metastasis by targeting HNRNPA1 to regulate glutamine metabolic reprogramming and angiogenesis.
1. Introduction
Colorectal cancer (CRC) is a prevalent type of gastrointestinal malignancy and is the third most frequently occurring cancer and the second leading cause of cancer-related death [1]. The invasion and migration of CRC are the main causes of death [2]. Therefore, understanding the molecular mechanism underlying CRC metastasis is crucial for discovering more efficient treatment approaches.
Long-chain noncoding RNAs (lncRNAs) are a category of RNA molecules whose length exceeds 200 nt and do not produce proteins, which are evolutionarily conserved [3]. LncRNA, as the largest class of noncoding transcripts, has a wide range of functions, affecting gene expression by regulating chromatin modification, protein synthesis, RNA maturation, and transport [4]. Studies have verified that alterations in the expressions of several lncRNAs occur in a variety of diseases, such as malignant tumors, affecting many biological functions and playing essential roles in the process of tumor formation [5]. The relationships between lncRNAs and CRC development and progression have been extensively discussed [6,7]. The ceRNA network associated with CRC has been identified through a comprehensive gene expression database, in which lncRNA 00114 (LINC00114) is highly expressed in CRC and is thought to be associated with overall survival [8]. Another study confirmed that LINC00114 effectively predicts overall survival and plays an important role in colon adenocarcinoma [9]. LINC00114 has been shown to be one of the lncRNA markers with the greatest prognostic value in CRC [10]. LINC00114 can promote the development of CRC by inhibiting EZH2/DNMT1-induced miR-133b expression [11]. Our bioinformatics analysis also revealed that LINC00114 is significantly overexpressed in CRC. In addition, studies have shown that LINC00114 can promote the progression of esophageal [12] and nasopharyngeal cancers [13]. However, whether LINC00114 participates in CRC metastasis and its mechanism are unclear.
Heterogeneous nuclear ribonucleoproteins (HNRNPs) are a group of RNA-binding proteins involved in various biological processes [14]. HNRNPA1, a highly prevalent and widely expressed constituent of this protein family, is involved in malignant transformation pathways [15]. In addition to promoting the expression of specific protein variants through selective mRNA splicing, HNRNPA1 is also responsible for controlling the levels and translation of crucial genes implicated in the progression of cancer [16,17]. Significant levels of HNRNPA1 have been observed in different cancer types [18,19]. Furthermore, HNRNPA1 is highly expressed in CRC and promotes aerobic glycolysis through pyruvate kinase M (PKM).
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Shiyu Tang, Meng Liu, Yangyang Zhu, Lifa Li, Chen Qing, Yuehua Guan, Tong Zhou, Xuegui Tang (2026). LINC00114 promotes colorectal cancer metastasis by targeting HNRNPA1 to regulate glutamine metabolism reprogramming and angiogenesis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025141
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Frequently Asked Questions
What is the role of LINC00114 in colorectal cancer metastasis?
LINC00114 promotes colorectal cancer metastasis by targeting HNRNPA1, which regulates glutamine metabolism reprogramming and angiogenesis.
How does LINC00114 affect glutamine metabolism in CRC?
LINC00114 positively regulates HNRNPA1 expression, which in turn modulates glutamine metabolism in CRC cells, contributing to metabolic reprogramming that supports metastasis.
What is the clinical significance of LINC00114 in colorectal cancer?
LINC00114 is highly expressed in CRC and correlates with poor prognosis. It serves as a potential prognostic biomarker and therapeutic target for inhibiting CRC metastasis.
How was the interaction between LINC00114 and HNRNPA1 confirmed?
The interaction was confirmed using an RNA-binding-protein immunoprecipitation (RIP) assay, which showed that LINC00114 binds to HNRNPA1 and positively regulates its expression.
What are the key findings of the in vivo study?
In vivo, intervention with LINC00114 repressed tumor progression and vascular normalization, and regulated glutamine metabolism, further supporting its role in CRC metastasis.
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