Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC

Li, **g-**g; Ru, Zi-xuan; Yang, Xu; Sun, **g-xue; Wu, Yan-mei-zhi; Yang, **ao-yao; Hou, Bo-yu; Xue, Bing; Ding, Chao; Qiao, Hong

doi:10.1186/s12967-024-05405-2

Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC

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Published: 20 June 2024

Volume 22, article number 586, (2024)
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Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC

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**g-**g Li¹,
Zi-xuan Ru¹,
Xu Yang¹,
**g-xue Sun¹,
Yan-mei-zhi Wu¹,
**ao-yao Yang²,
Bo-yu Hou¹,
Bing Xue¹,
Chao Ding³ &
…
Hong Qiao^1,4

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Abstract

The prevalence of papillary thyroid cancer (PTC) has been rising in recent years. Despite its relatively low mortality, PTC frequently metastasizes to lymph nodes and often recurs, posing significant health and economic burdens. The role of iodine in the pathogenesis and advancement of thyroid cancer remains poorly understood. Circular RNAs (circRNAs) are recognized to function as competing endogenous RNAs (ceRNAs) that modulate gene expression and play a role in various cancer stages. Consequently, this research aimed to elucidate the mechanism by which circRNA influences the impact of iodine on PTC. Our research indicates that high iodine levels can exacerbate the malignancy of PTC via the circ_0004851/miR-296-3p/FGF11 axis. These insights into iodine’s biological role in PTC and the association of circRNA with the disease could pave the way for novel biomarkers and potentially effective therapeutic strategies to mitigate PTC progression.

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Introduction

On a global scale, thyroid cancer (TC) is recognized as the most prevalent endocrine malignancy. Recent decades have seen a steady incline in TC incidence [1], with papillary thyroid cancer (PTC)—prevalent in iodine-sufficient regions like China—constituting over 70% of these cases [2]. PTC, typically highly differentiated, boasts a post-5-year survival rate exceeding 90% [3]. However, recurrence occurs in 10-15% of PTC cases, significantly impacting survival and life quality for these patients.

Iodine significantly influences PTC development, with its role in thyroid cell proliferation and differentiation being well-documented. Abnormal iodine levels, either deficient or excessive, are implicated in thyroid pathology [4]. Epidemiological evidence suggests a higher PTC incidence in iodine-deficient than in iodine-excess regions, indicating iodine’s critical role in thyroid cancer progression [5]. Furthermore, the BRAF V600E gene mutation is the most common genetic mutation in PTC, with an average incidence of about 45% [6]. Interestingly, previous studies have concluded that among the iodine metabolism genes, BRAF V600E is a highly specific target for PTC [7]. Nonetheless, the impact of high iodine levels on existing thyroid cancer and its underlying mechanisms warrant further investigation.

Non-coding RNAs (ncRNAs) is identified as pivotal in tumorigenesis, encompassing various forms such as transfer RNAs, ribosomal RNAs, long ncRNAs (lncRNAs), small ncRNAs—including microRNAs, piRNAs, snoRNAs, snRNAs, exRNAs—and circular RNAs (circRNAs) [8]. CircRNAs, a novel class of ncRNAs, are gaining prominence as clinical biomarkers due to their differential expression in tumors and associations with diagnosis and prognosis [Full size image

Silencing of mir-296-3p reverses the effects of si-circ_0004851 in PTC cells

Considering our hypothesis that circ_0004851 primarily modulates PTC progression by sequestering miR-296-3p, it was crucial to investigate whether miR-296-3p could counteract the impact of si-circ_0004851 on PTC cells. We conducted rescue experiments in TPC-1 and BCPAP cells co-transfected with si-circ_0004851 and si-NC, using a miR-296-3p inhibitor or control vector. qRT-PCR and western blot analyses demonstrated (Fig. 7A-B) that circ_0004851 knockdown in PTC cells resulted in the inhibition of FGF11 expression, while the miR-296-3p inhibitor reversed the inhibitory effect of si-circ_0004851 on FGF11. CCK-8 assessment revealed that exogenous down-regulation of miR-296-3p expression counteracted the growth inhibitory effect of si-circ_0004851 (Fig. 7C). In comparison to the NC group, miR-296-3p inhibition and si-circ_0004851 co-transfection partially rescued the impaired motility of si-circ_0004851 in PTC cell lines, as evidenced by cell scratch migration assays and Transwell invasion assays (Fig. 7C-D). Furthermore, apoptosis assays confirmed that miR-296-3p inhibition, along with si-circ_0004851, mitigated the apoptotic effect of si-circ_0004851 in PTC cells (Fig. 7F). Western blot also showed that miR-296-3p inhibition reversed the up-regulation of si-circ_0004851 on apoptosis-related proteins in PTC cells (Fig. 7G).

Circ_0004851’s impact on PTC progression through FGF11

Although FGF11 has been identified as an oncogene in a number of cancer types, its function in PTC is unknown. In order to elucidate the association involving endogenous FGF11 expression and PTC pathogenesis, we generated an FGF11 overexpression plasmid and transfected it into circ_0004851-silenced TPC-1 and BCPAP cells. This aimed to investigate whether circ_0004851 influences PTC progression by targeting FGF11. We assessed proliferative, migratory, invasive, and apoptotic capabilities to delve into the effects of FGF11 overexpression on circ_0004851-deficient PTC cells. qRT-PCR and Western blot analyses demonstrated that the FGF11 overexpression plasmid significantly upregulated FGF11 expression. Furthermore, the overexpression of FGF11 upregulated circ_0004851-deficient cellular FGF11 expression (Fig. 8A-B). In addition, we observed that the proliferation, migration, and invasion abilities of cells, as assessed by cck-8, cell scratch, and Transwell assays, were enhanced upon FGF11 overexpression, while apoptosis was inhibited when compared to cells treated with the NC group. Moreover, overexpression of FGF11 in circ_0004851-deficient cells mitigated the inhibitory effects of si-circ_0004851 on proliferation, migration, invasion, and promoted apoptotic effects (Fig. 8C-F). Collectively, these findings suggest that circ_0004851 primarily contributes to PTC progression by targeting FGF11.

Establishment of a nude mouse model to investigate high iodine’s promotion of PTC cell growth in vitro

Elevated levels of iodine are strongly implicated in thyroid cancer development [20]. To elucidate the role of high iodine in PTC progression, we established a xenograft tumor model. As depicted in Fig. 9A-B, the tumor volume and weight of mice in the high-iodine group exceeded those in the control group (p less than 0.05). Notably, the mice’s weight did not significantly differ between the two groups throughout the experiment (Fig. 9C). Furthermore, PCR and Western blot outcomes revealed that circ_0004851 expression elevated, while miR-296-3p expression reduced in the high iodine group. Additionally, FGF11 mRNA and protein expression levels were elevated in the high iodine group (Fig. 9D-E). These outcomes indicate that high iodine promotes tumor growth in the xenograft tumor model and significantly influences the expression of circ_0004851/miR-296-3p/FGF11 in this model.

Discussion

Iodine is vital for life and represents the most universally essential element for all living organisms. However, excessive iodine intake can have adverse health consequences. Studies have demonstrated that excess iodine can lead to benign thyroid disorders, including autoimmune thyroiditis, benign thyroid nodules, hypothyroidism, and hyperthyroidism [21]. Paradoxically, elevated iodine intake appears to result in less aggressive thyroid cancer, particularly PTC [22]. Guan H et al. investigated the relationship between iodine intake and BRAF mutations in PTC and showed that the prevalence of BRAF mutations in PTC patients with high iodine intake was 69%, which was higher than the patients with normal iodine intake [23]. A Korean study found that both relatively excessive iodine intake and low iodine intake appear to be important risk factors for BRAF mutations in PTC patients [24]. A recent Meta-Analysis study found that the incidence of BRAF V600E mutations in PTC patients with high iodine intake was 77.6%, which was higher than 64.61% in patients with low iodine intake and 60.15% in patients with normal iodine intake [7]. Despite a considerable body of research on the impact of iodine on thyroid cancer tumorigenesis and progression, the association involving high iodine intake and TC risk remains contentious, and the mechanisms behind iodine excess in the development of PTC are still unclear [25,26,27,28,29,30,31,32,33,34]. Serum iodine levels reflect the actual iodine content in the body, offering a more accurate assessment of iodine nutritional status. Unlike urinary iodine, serum iodine is more stable and less susceptible to dietary fluctuations. Therefore, we opted to utilize blood iodine levels as a basis for evaluating the iodine nutritional status of the subjects in our research. Through clinical data assessment and a series of in vitro as well as in vivo experiments, we have established that elevated iodine levels contribute to the development of PTC. Furthermore, we identified the involvement of the circ_0004851/miR-296-3p/FGF11 axis in mediating the effects of iodine on PTC in our in vitro mechanistic investigation (Fig. 10).

In our research population, elevated blood iodine levels emerge as a risk factor for PTC. Our findings indicate that high blood iodine levels correlate with various aspects of PTC, including tumor location, size, number, and metastasis. Patients with elevated blood iodine values tend to present with enlarged and multiple tumors. This conclusion aligns with the outcomes of studies, such as one assessing serum iodine concentration, which classifies high serum iodine levels as a risk factor for thyroid diseases [35]. Another research suggests that high iodine intake could be linked to the growth of PTC rather than its initiation [31]. A meta-assessment of 22 cross-sectional studies conducted by Yan et al. indicates that high iodine intake does not pose a risk for PTC development and that high urinary iodine is a specific characteristic of the disease [36]. Some studies have identified associations between excessive iodine intake and elevated risks of lymph node metastasis, larger tumors, peritumoral invasion, bilateral tumor location, and extra-thyroidal metastases. However, others have failed to establish such associations regarding lymph node metastasis, tumor size, multifocal tumors, or bilateral and extra-peritumoral extension [5, 37,38,39,40]. The inconsistency in previous studies’ findings on the association involving dietary iodine intake as well as thyroid cancer outcomes from variations in measurement methods and potential measurement biases associated with assessing iodine intake [41, 42].

In our research, we observed that iodine at large concentrations inhibited apoptosis while promoting proliferation, migration, and invasion of PTC cells. Previous research reported that TPC-1 cells containing 100 μm Ki (high iodine) exhibited significantly elevated proliferation and migration compared to a cell line containing 25 μm Ki [15]. Additionally, KIO₃ was found to have a tumor-promoting effect (elevated migration and invasion) on SW579 (a human thyroid cancer cell line) cells at a concentration of 10^− 6 mol/L, aligning with our research’s outcomes [17]. Our mouse experiments corroborate the findings of Lv et al. [43] that exposure to 2 mmol/L KIO₃ for 72 h elevated the proliferation of thyroid cancer cells (BCPAP and 8305 C) and that high iodine promoted tumor growth in a mouse transplantation tumor model. elevated iodine concentrations promote the proliferation of PTC cells, as indicated by a heightened rate of proliferation [44]. Therefore, it is reasonable to infer that elevated iodine intake exerts a significant influence on PTC development.

Our research identified dysregulation of numerous circRNAs, miRNAs, and mRNAs in PTC tissues from patients exposed to high iodine. Some of these miRNAs and mRNAs have previously been implicated in the mechanism of PTC progression under high iodine conditions [45]. Consequently, we postulate that the differentially expressed genes identified through RNA sequencing in iodine-exposed PTC tissues could play a role in the progression of PTC tissues.

CircRNAs play a significant functional role in tumorigenesis [46, 47]. Although circRNA research is still in its early stages and their roles in PTC occurrence and progression are not well-understood, a growing number of novel circRNAs have been identified that could have oncogenic roles in thyroid cancer [48]. In addition to direct protein interactions, circRNAs contribute to TC progression by acting as miRNA sponges. For instance, the overexpression of circ-PSD3 sponges miR-7-5p in PTC, reducing the inhibition of METTL7B by miR-7-5p, thereby promoting the proliferation and invasion of PTC cells [49]. Similarly, circular RNA circRUNX1 promotes PTC progression and metastasis by sponging miR-296-3p and regulating DDHD2 expression [50]. Circ-0001018, circ-0006156, circ_0058124, and circ_0062389 have been implicated in the regulation of various signaling pathways associated with TC cell proliferation and apoptosis [51,52,53,54]. In our research, we investigated iodine’s role in PTC progression through the circ_0004851-associated ceRNA network (circ_0004851/miR-296-3p/FGF11 axis) using RNA sequencing, which we subsequently validated in PTC tissues, cells, and xenograft tumor mice. We focused on a specific circRNA, circ-0004851, which plays a pivotal role in PTC. We observed high expression levels of circ_0004851 in both PTC tissues and cells, consistent with our high-throughput sequencing outcomes for PTC tissues. This led us to hypothesize that circ_0004851 could play a crucial role in PTC progression. Initially, we elucidated the structure of circ_0004851 in PTC. Following the down-regulation of circ_0004851 through RNA interference, we observed reduced proliferation, invasion, and migration in PTC cells, accompanied by elevated apoptosis. Circ-0004851 was abundantly expressed in PTC under high iodine exposure, contributing to worse biological behavior at elevated levels. These findings suggest that changes in PTC cell behavior due to high iodine are associated with regulated circ_0004851 levels, highlighting its pivotal role in PTC progression. In our research, we found that miR-296-3p exhibited a strong binding affinity to both circ-0004851 and FGF11, a relationship confirmed through bioinformatics, qPCR, luciferase, and FISH analyses. This underscores the significant role of miR-296-3p in thyroid tumor progression and metastasis. Mechanistic studies further revealed that a miR-296-3p inhibitor reversed the downregulation of FGF11 expression induced by circ-0004851 knockdown in PTC cells, along with the inhibition of PTC progression in vitro. These outcomes establish a novel association between miR-296-3p, circ-0004851, and the regulation of PTC. Circ-0004851 acts as a sponge for miR-296-3p and miR-296-3p as a critical negative regulator of FGF11, suggesting a network regulatory relationship among circ-0004851, miR-296-3p, and FGF11 in PTC. FGF11 was significantly upregulated in PTC under high iodine exposure, and its overexpression promoted tumor cell proliferation, invasion, migration, and inhibited apoptosis. This indicates a close connection between FGF11 and PTC development and biological characteristics. FGF11 expression, a target of miR-296-3p, was positively regulated by circ-0004851 in rescue experiments, and the suppression of circ-0004851 mitigated the tumor-promoting effects of overexpressed FGF11. The outcomes underscore the function of FGF11 to promote PTC cell progression and further validate circ-0004851 as a ceRNA for miR-296-3p, providing valuable evidence for the involvement of circ-0004851 in PTC development. These findings unveil an unreported correlation between FGF11, miR-296-3p, and circ-0004851, culminating in the identification of a mechanism where circ-0004851 functions as a miR-296-3p sponge to drive PTC development.

Hypoxia is a significant cause of metastasis and recurrence in cervical lymph nodes of PTC, and mechanistic studies reveal that in a hypoxic environment, FGF11 forms a positive feedback loop with HIF1α, which in turn promotes thyroid cancer growth and metastasis [55]. However, no study has yet demonstrated the positive feedback loop between circ-0004851 and miR-296-3p has a regulatory relationship with HIF1α. A study has identified the role of miR-296-3p in targeting ether-à-go-go (EAG1) to regulate cell growth in human glioblastoma [56], while EAG1 can promote tumor angiogenesis by increasing HIF1 activity [57]. In Chinese hamster ovary cells and mouse embryonic fibroblasts, HIF-1α levels were similarly elevated by EAG1 expression [58]. In addition, in non-small cell lung cancer, miR-296-3p acts as a tumor suppressor and inhibits tumor cell migration and invasion by targeting apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) expression [59], and APEX1 can further promote the transcriptional activation of HIF1 or hypoxia-inducible factor-like factor (HLF) as a hypoxia-related gene [60]. The above findings suggest that miR-296-3p may indirectly regulate the level of HIF1α by targeting and regulating its downstream genes.

Iodine intake may induce BRAF V600E gene mutations in PTC patients through various indirect pathways [7]. However, the effect of BRAF V600E gene mutation on the circ-0004851/miR-296-3p/FGF11 pathway is unknown. Previous studies have found that the BRAF V600E mutation in PTC is associated with glucose transporter 1 (GLUT1) overexpression, which may contribute to the initiation of a glycolytic phenotype in cancer cells [61]. The YAP/HIF-1α complex binds to the GLUT1 gene and directly activates its transcription, which accelerates the PTC cells’ glycolysis under hypoxic conditions [62]. The above findings suggest that BRAF mutations may enhance the circ_0004851/miR-296-3p/FGF11 pathway by affecting the binding of GLUT1 to the YAP/HIF-1α complex.

In this research, we included a substantial number of clinical cases, enabling a comprehensive exploration of the association involving high iodine as well as the clinical characteristics of PTC patients. Our investigation extended to the cellular level, where we validated that iodine’s effects on various biological behaviors align with the clinical data. Leveraging the advantages of high-throughput sequencing, such as speed, accuracy, and efficiency, we delved into the molecular mechanism through which iodine influences PTC. Following repeated interventions on upstream and downstream genes and thorough validation of their effects on biological behaviors, we established the mechanism by which iodine affects PTC. However, it’s important to acknowledge the limitations of this research. Determination of circulating serum iodine in patients is a tricky issue, and iodine levels are dependent on the patient’s living environment and diet. In the present study, we did not assess serum iodine levels in patients before the onset of PTC, nor did we continuously observe the dynamics of serum iodine levels, which may affect some of the conclusions about the relationship between their levels and tumor characteristics. Similarly, we assessed the impact of various concentrations of KIO₃ on normal thyroid cells and malignant PTC cells, yet we did not investigate the time-dependent effects of KIO₃ across various cell lines at various time points. This aspect should be considered in our future research. Another limitation pertains to our classification; we focused solely on papillary thyroid carcinoma, failing to examine multiple thyroid cancer subtypes and explore the effects and molecular mechanisms of high iodine on PTC in these subtypes. Furthermore, the critical next step involves conducting live animal experiments to intervene with circ_0004851/miR-296-3p/FGF11 and validate its molecular mechanism. Finally, the translational significance of our findings in the clinical context requires further confirmation.

Conclusion

In summary, our data confirm that high iodine regulates tumor progression in PTC through the circ_0004851/miR-296-3p/FGF11 pathway. With the global focus on iodine and thyroid cancer, our findings provide further evidence for the role of iodine in PTC and enrich the research of non-coding RNAs in iodine-related thyroid cancer. Additionally, we suggest that targeting the circ_0004851/miR-296-3p/FGF11 axis is a potential strategy for the treatment of PTC, and that circRNA silencing through the ceRNA mechanism could play a crucial therapeutic role in resisting high iodine-promoted tumor progression.

Data availability

As the initial contributions detailed in the research are presently undergoing additional evaluation in preparation for their submission to additional funding initiatives, they have not yet been made available in public databases. Please contact the corresponding author with the applicable justifications if necessary. We shall disclose our data provided that no conflicts arise.

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Acknowledgements

For their invaluable assistance in conducting this research, we extend our heartfelt gratitude to The Second Affiliated Hospital of Harbin Medical University and the Key Lab of Etiology and Epidemiology, Education Bureau of Heilongjiang Province & Ministry of Health of P. R. China, Harbin Medical University.

Funding

The grants 82373698 and 82073491 from the National Natural Science Foundation of China, the LH2021H062 grant from the Heilongjiang Provincial Natural Science Foundation of China, and the 2020 − 227 grant from the Heilongjiang Provincial Health Commission Foundation of China all contributed to the funding for this research.

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Authors and Affiliations

Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, China
**g-**g Li, Zi-xuan Ru, Xu Yang, **g-xue Sun, Yan-mei-zhi Wu, Bo-yu Hou, Bing Xue & Hong Qiao
Department of Science and Education, Heilongjiang Provincial Hospital, Harbin, 150036, Heilongjiang, China
**ao-yao Yang
Department of General surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, Heilongjiang, China
Chao Ding
NHC Key Laboratory of Etiology and Epidemiology, Harbin Medical University, No. 157 Baojian Road, Nangang District, Harbin, 150081, Heilongjiang, China
Hong Qiao

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**g-**g Li
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Zi-xuan Ru
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Xu Yang
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**g-xue Sun
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Yan-mei-zhi Wu
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**ao-yao Yang
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Bing Xue
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Chao Ding
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Hong Qiao
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Contributions

The concept for this manuscript originated at HQ. Experiments were conducted by JL, who also composed the manuscript. ZR, XY, JS, YW, and XY were responsible for the collection and assessment of the clinical data. The tissues were collected by BH, BX, and CD. The manuscript was jointly authored and endorsed by all contributors.

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Correspondence to Hong Qiao.

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The Human Subjects Studies (No. KY2020-022) were subject to evaluation and received approval from the Ethics Committee of the Second Affiliated Hospital of Harbin Medical University, China. Prior to their involvement in this research, the patients/participants were granted written informed consent.

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Li, Jj., Ru, Zx., Yang, X. et al. Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC. J Transl Med 22, 586 (2024). https://doi.org/10.1186/s12967-024-05405-2

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Received: 03 April 2024
Accepted: 14 June 2024
Published: 20 June 2024
DOI: https://doi.org/10.1186/s12967-024-05405-2

Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC

Abstract

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miRNAs in pancreatic cancer progression and metastasis

The Diagnostic and Prognostic Value of miR-155 in Cancers: An Updated Meta-analysis

The microRNA Let-7 and its exosomal form: Epigenetic regulators of gynecological cancers

Introduction

Silencing of mir-296-3p reverses the effects of si-circ_0004851 in PTC cells

Circ_0004851’s impact on PTC progression through FGF11

Establishment of a nude mouse model to investigate high iodine’s promotion of PTC cell growth in vitro

Discussion

Conclusion

Data availability

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding author

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Ethics approval and consent to participate

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Competing interests

Additional information

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Electronic supplementary material

Supplementary Material 1

Supplementary Material 2

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Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC

Abstract

Similar content being viewed by others

miRNAs in pancreatic cancer progression and metastasis

The Diagnostic and Prognostic Value of miR-155 in Cancers: An Updated Meta-analysis

The microRNA Let-7 and its exosomal form: Epigenetic regulators of gynecological cancers

Introduction

Silencing of mir-296-3p reverses the effects of si-circ_0004851 in PTC cells

Circ_0004851’s impact on PTC progression through FGF11

Establishment of a nude mouse model to investigate high iodine’s promotion of PTC cell growth in vitro

Discussion

Conclusion

Data availability

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding author

Ethics declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Additional information

Publisher’s Note

Electronic supplementary material

Supplementary Material 1

Supplementary Material 2

Rights and permissions

About this article

Cite this article

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