Key Takeaways & Executive Findings
- •• HNF1A-AS1 is upregulated in epithelial ovarian cancer (EOC) cells and acts as a competing endogenous RNA (ceRNA) by sponging miR-214, thereby relieving miR-214-mediated suppression of SEMA4D signaling. • Overexpression of HNF1A-AS1 promotes EOC cell proliferation, migration, invasion, and tumor growth in xenograft models, while knockdown suppresses these malignant phenotypes. • HNF1A-AS1 drives M2 macrophage polarization in the tumor microenvironment, an effect that is reversed by miR-214 overexpression or SEMA4D silencing, highlighting a novel immunomodulatory mechanism. • The HNF1A-AS1/miR-214/SEMA4D axis represents a promising therapeutic target for EOC, offering potential for combined anti-tumor and immunomodulatory strategies.
Abstract
To determine whether lncRNA HNF1A-AS1 affects epithelial ovarian cancer (EOC) growth and macrophage polarization through miR-214/SEMA4D, the endogenous HNF1A-AS1 and miR-214 levels in human EOC cell lines are compared with those in normal ovarian epithelial IOSE80 cells. HNF1A-AS1 is overexpressed or silenced to investigate whether HNF1A-AS1 regulates miR-214/SEMA4D in SKOV3 cells and xenograft tumors, as well as the phenotypic switching of THP-1 cells. Compared with IOSE80 cells, EOC cells present significantly higher HNF1A-AS1 level and lower miR-214 level. Fluorescence in situ hybridization reveals predominant cytoplasmic localization of HNF1A-AS1, supporting its role as a competing endogenous RNA. HNF1A-AS1 and miR-214 antagonize each other in SKOV3 cells. In vitro, HNF1A-AS1 inhibits SKOV3 apoptosis and promotes migration and invasion. HNF1A-AS1 overexpression enhances miR-214 downstream of SEMA4D/PLEXIN-B1/TIAM1/RAC signaling, but miR-214 mimics significantly reverses this effect. Compared with control tumors, xenograft tumors derived from HNF1A-AS1-overexpressing SKOV3 cells present increased tumor growth, attenuated miR-214 expression, and activated SEMA4D/PLEXIN-B1/TIAM/RAC signaling. Knockdown of HNF1A-AS1 has the opposite effects. Additionally, HNF1A-AS1 promotes M2 phenotypic switching in THP-1 cells, which could be reversed by miR-214 overexpression or SEMA4D silencing. Our study suggests that by antagonizing miR-214, HNF1A-AS1 activates the SEMA4D/PLEXIN-B1/TIAM/RAC pathway, facilitating EOC growth and potentially promoting M2 macrophage polarization in the tumor microenvironment. HNF1A-AS1 represents a compelling therapeutic target for treating EOC.
1. Introduction
Globally, ovarian cancer ranks among the prevalent cancer types and is characterized by a 5-year survival rate ranging from 30% to 40% [1,2]. Epithelial ovarian cancer (EOC) accounts for approximately 95% of all ovarian cancer cases [2]. Metastasis is the main cause of EOC-related death. Early-stage EOCs often remain asymptomatic, leading to a diagnosis at advanced stages with metastases throughout the peritoneum in 60% to 80% of cases [3]. The molecular mechanisms involved in EOC progression and metastasis must be revealed to reduce EOC-related deaths.
MicroRNAs (miRNAs) are short noncoding RNAs that negatively regulate posttranscriptional gene expression by binding to the untranslated region of specific mRNA targets through base pairing [4]. Human EOC tissue and cell lines express significantly less miR-214 than normal controls do, according to our previous study [5]. Semaphorin 4D (SEMA4D) belongs to the class 4 semaphorin family and facilitates angiogenesis during tumor growth and metastasis by interacting with PLEXIN-B1. miR-214 inhibits EOC cell proliferation while promoting apoptosis by targeting SEMA4D [6,7]. PLEXIN-B1 is also a target of miR-214, which acts as an oncogene in cervical cancer [8]. Upon binding to PLEXIN-B1, SEMA4D recruits T lymphoma invasion and metastasis 1 (TIAM1), activating rho GTPase RAC1/p21-activated kinase (PAK) signaling [9]. Therefore, the loss of miR-214 may increase tumor development and metastasis in gynecologic cancer by activating SEMA4D/PLEXIN-B1/TIAM1/RAC. However, the mechanism underlying miR-214 deficiency in EOC cells is unknown.
Long noncoding RNAs (lncRNAs) are RNA molecules that lack protein-coding potential and consist of more than 200 nucleotides [10]. In human diseases, including EOC, lncRNAs act as competing endogenous RNAs or miRNA sponges to counter miRNA-mediated gene silencing [11]. HNF1A antisense RNA 1 (HNF1-AS1) has emerged as a newly discovered lncRNA comprising 2455 nucleotides. Although earlier studies reported HNF1-AS1 as an oncogene in many types of cancer [12–14], its involvement in EOC remains unknown. HNF1A-AS1 contains three miR-214 binding sites and promotes esophageal cancer growth and metastasis by counteracting the miR-214-mediated suppression of SRY-box transcription factor 4 [15]. Accordingly, we speculated that endogenous HNF1A-AS1 might be responsible for the reduced miR-214 expression in EOC, thus activating the SEMA4D/PLEXIN-B1/TIAM1/RAC pathway.
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Yang Liu, Yanzhi Wu, Yujie Gengxiao, Yan Li, Jiamei Song, Chunyi Sun (2026). Long noncoding RNA HNF1A-AS1 promotes ovarian cancer growth and M2 macrophage polarization by counteracting miR-214-mediated suppression of semaphorin 4D signaling. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025208
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Frequently Asked Questions
What is the role of HNF1A-AS1 in ovarian cancer?
HNF1A-AS1 is a long noncoding RNA that is upregulated in epithelial ovarian cancer (EOC) cells. It acts as a competing endogenous RNA (ceRNA) by sponging miR-214, thereby relieving miR-214-mediated suppression of SEMA4D signaling. This promotes EOC cell proliferation, migration, invasion, and tumor growth, and also drives M2 macrophage polarization in the tumor microenvironment.
How does HNF1A-AS1 interact with miR-214?
HNF1A-AS1 contains three binding sites for miR-214 and functions as a molecular sponge, sequestering miR-214 and preventing it from binding to its target mRNAs, such as SEMA4D. This counteracts the suppressive effect of miR-214 on SEMA4D expression, leading to activation of downstream signaling pathways.
What is the clinical significance of the HNF1A-AS1/miR-214/SEMA4D axis?
The HNF1A-AS1/miR-214/SEMA4D axis plays a critical role in EOC progression and immune evasion. Targeting this axis, for example by silencing HNF1A-AS1 or restoring miR-214 expression, could inhibit tumor growth and modulate the tumor microenvironment, offering a promising therapeutic strategy for EOC.
How does HNF1A-AS1 affect macrophage polarization?
HNF1A-AS1 promotes M2 phenotypic switching in THP-1 macrophages, which is associated with an immunosuppressive tumor microenvironment. This effect is reversed by miR-214 overexpression or SEMA4D silencing, indicating that HNF1A-AS1 acts through the miR-214/SEMA4D pathway to influence macrophage polarization.
What methods were used in this study?
The study used human EOC cell lines (SKOV3, OVCAR-3) and normal ovarian epithelial IOSE80 cells. Techniques included fluorescence in situ hybridization (FISH) to localize HNF1A-AS1, overexpression and knockdown experiments, xenograft tumor models, and assays for apoptosis, migration, invasion, and macrophage polarization.
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