Key Takeaways & Executive Findings
- •• miR-34b-3p is downregulated in cisplatin-resistant cervical cancer cells and tissues, and its overexpression suppresses proliferation, migration, invasion, and enhances chemosensitivity. • STC2 and FN1 are identified as direct targets of miR-34b-3p, and their expression is elevated in resistant cells, contributing to chemoresistance and aggressive phenotypes. • Rescue experiments confirm that STC2 or FN1 overexpression partially reverses the tumor-suppressive effects of miR-34b-3p, validating the miR-34b-3p/STC2/FN1 axis. • The miR-34b-3p/STC2 or FN1 axis represents a potential therapeutic target for overcoming cisplatin resistance in cervical cancer patients.
Abstract
Dysregulation of microRNA (miRNA) expression in cancer is a significant factor contributing to the progression of chemoresistance. The objective of this study is to explore the underlying mechanisms by which miR-34b-3p regulates chemoresistance in cervical cancer (CC). Previous findings have demonstrated low expression levels of miR-34b-3p in both CC chemoresistant cells and tissues. In this study, we initially characterize the behavior of SiHa/DDP cells which are CC cells resistant to the chemotherapeutic drug cisplatin (DDP). Subsequently, miR-34b-3p mimics are transfected into SiHa/DDP cells. It is observed that overexpression of miR-34b-3p substantially inhibits the proliferation, migration, and invasion abilities of SiHa/DDP cells and also enhances their sensitivity to DDP-induced cell death. Quantitative RT-PCR and western blot analysis further reveal elevated expression levels of STC2 and FN1 in SiHa/DDP cells, contrary to the expression pattern of miR-34b-3p. Moreover, STC2 and FN1 contribute to DDP resistance, proliferation, migration, invasion, and decreased apoptosis in CC cells. Through dual-luciferase assay analysis, we confirm that STC2 and FN1 are direct targets of miR-34b-3p in CC. Finally, rescue experiments demonstrate that overexpression of either STC2 or FN1 can partially reverse the inhibitory effects of miR-34b-3p overexpression on chemoresistance, proliferation, migration and invasion in CC cells. In conclusion, our findings support the role of miR-34b-3p as a tumor suppressor in CC. This study indicates that targeting the miR-34b-3p/STC2 or FN1 axis has potential therapeutic implications for overcoming chemoresistance in CC patients.
1. Introduction
Cervical cancer (CC) is a major global health concern and is the fourth most common malignancy in females [1]. Despite advancements in vaccination, screening, and treatment, the 3- to 5-year surviving ratio in developing countries remains less than 50% [2]. Platinum-based combination chemotherapy is an important adjuvant treatment for CC [3]. However, the development of chemoresistance to the first-line chemotherapeutic drug cisplatin (DDP) has significantly impacted patient prognosis [4]. The mechanisms underlying DDP-resistance in CC are still not fully understood, highlighting the need for a better understanding of the mechanism in CC DDP-resistance to develop more effective therapies.
MicroRNAs (miRNAs) are small noncoding RNA molecules that function as negative regulators of mRNA expression [5]. They exert post-transcriptional regulation through complementary base pairing with target gene mRNAs [6]. One miRNA can target multiple genes, and multiple miRNAs also can regulate the same target gene [7]. While previous studies have investigated the function of miR-34b-3p in the development of various cancers, such as renal cell carcinoma and endometrial cancer [8], its specific involvement in CC chemoresistance remains poorly understood.
In our previous study, we found that the expression of STC2 is inversely correlated with that of miR-34b-3p in SiHa/DDP cells and that miR-34b-3p can target STC2, suggesting that miR-34b-3p may mediate CC resistance through STC2 [9]. In the present study, we identified fibronectin 1 (FN1) as another target gene of miR-34b-3p. To further investigate the functions and potential mechanism of miR-34b-3p in CC chemoresistance, we examined how miR-34b-3p modulates CC chemoresistance by targeting both STC2 and FN1. Our findings provide novel insights into CC chemoresistance and new clues for discovering screening markers and developing therapeutic strategies for CC treatment.
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Shanshan Jin, Wenting Wang, Xinrui Xu, Zhaowei Yu, Zihan Feng, Jun Xie, Huimin Lv (2026). miR-34b-3p-mediated regulation of STC2 and FN1 enhances chemosensitivity and inhibits proliferation in cervical cancer. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024009
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Frequently Asked Questions
What is the role of miR-34b-3p in cervical cancer chemoresistance?
miR-34b-3p acts as a tumor suppressor in cervical cancer. It is downregulated in cisplatin-resistant cells and tissues, and its overexpression inhibits proliferation, migration, invasion, and enhances chemosensitivity to cisplatin by targeting STC2 and FN1.
How does miR-34b-3p regulate STC2 and FN1 expression?
miR-34b-3p directly binds to the 3' untranslated regions of STC2 and FN1 mRNAs, leading to their degradation or translational repression, thereby reducing their protein levels.
What are the clinical implications of this study?
The study suggests that targeting the miR-34b-3p/STC2 or FN1 axis could be a potential therapeutic strategy to overcome cisplatin resistance in cervical cancer patients, improving treatment outcomes.
What methods were used to validate the targeting of STC2 and FN1 by miR-34b-3p?
Dual-luciferase reporter assays were used to confirm that STC2 and FN1 are direct targets of miR-34b-3p. Additionally, quantitative RT-PCR and western blot analyses showed inverse expression patterns.
What is the significance of the rescue experiments in this study?
Rescue experiments demonstrated that overexpression of either STC2 or FN1 partially reversed the inhibitory effects of miR-34b-3p on chemoresistance, proliferation, migration, and invasion, confirming the functional relevance of these targets.
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