INAVA promotes aggressiveness of papillary thyroid cancer by upregulating MMP9 expression

Guan, Hongyu; Guo, Yan; Liu, Liehua; Ye, Runyi; Liang, Weiwei; Li, Hai; **ao, Haipeng; Li, Yanbing

doi:10.1186/s13578-018-0224-4

INAVA promotes aggressiveness of papillary thyroid cancer by upregulating MMP9 expression

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Published: 05 April 2018

Volume 8, article number 26, (2018)
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INAVA promotes aggressiveness of papillary thyroid cancer by upregulating MMP9 expression

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Hongyu Guan¹^na1,
Yan Guo¹^na1,
Liehua Liu¹^na1,
Runyi Ye²,
Weiwei Liang¹,
Hai Li¹,
Haipeng **ao¹ &
…
Yanbing Li¹

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Abstract

Background

Innate immunity activator (INAVA) has been shown to be elevated in lung adenocarcinoma. However, its expression pattern and function in papillary thyroid cancer (PTC) are unknown. This study aimed to identify the clinical, biological, and mechanistic impacts of INAVA on PTC.

Methods

Using The Cancer Genome Atlas dataset, real time PCR, and immunohistochemistry, the expression of INAVA in PTC was analyzed. Gain- and loss-of-function assays were performed to investigate the role of INAVA in PTC cell invasion, migration, and metastasis. We explored the molecular mechanisms underlying the roles of INAVA in PTC cells using transcriptome resequencing, real time PCR, western blotting and immunohistochemistry.

Results

We found that INAVA expression was significantly upregulated in PTC and was significantly associated with lymph node metastasis. Loss- and gain-of-function experiments demonstrated that INAVA promoted the aggressive phenotype of PTC cells in vitro and in vivo. Mechanistic study suggested that upregulation of INAVA resulted in elevated fibroblast growth factor 1 (FGF1), which in turn increased the expression level of matrix metalloproteinases 9 (MMP9). We further identified that the level of INAVA was positively correlated with the levels of FGF1 and MMP9 in clinical PTC specimens.

Conclusion

These data establish a novel role for INAVA in promoting PTC progression and suggest that INAVA may represent a therapeutic target for the disease.

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Background

Thyroid cancer is the most common type of endocrine-related malignancy and shows rapidly increasing incidences during the past decades [1]. Papillary thyroid cancer (PTC) is the most common form of thyroid cancer, representing 70–80% of all thyroid cancer [2]. In most cases, patients with PTC follow an indolent course and have excellent prognosis [3]. However, extrathyroidal extension and distant metastasis are extremely important risk factors for PTC and are still major clinical challenges [4, 5]. Thus, a good understanding of the molecular alterations responsible for aggressive behavior of PTC is still imperative.

Tumor metastasis is a multistep process during which a subset of cancer cells disseminate from the site of a primary tumor and establish secondary tumors at distant sites [6]. Matrix metalloproteinases (MMPs) are proteolytic enzymes responsible for remodeling extracellular matrix (ECM) in many physiological and pathological processes [7]. Moreover, besides its role in degradation of ECM molecules, MMPs play important roles in multiple aspects of cancer progression, including tumor growth, almost all metastatic steps, and angiogenesis [8, 9]. MMP9, one of the best characterized members in MMP family, is well known to degrade ECM and is closely related to the cancer invasion and metastasis [10]. In PTC, Ahmed et al. showed that silencing of FoxM1 inhibited migration and invasion of PTC cells via decreasing the expression levels of MMP9 and MMP2 [11]. Moreover, the expression level of arachidonate 5-lipoxygenase (ALOX5) was upregulated in PTC and it promoted PTC cell invasion through increased secretion of MMP9 [Full size image

Table 1 Association between INAVA expression and clinicopathologic parameters in PTC patients using TCGA dataset

Full size table

Table 2 Association between INAVA expression and clinicopathologic parameters in PTC patients

Full size table

Overexpression of INAVA promotes PTC cells invasion, migration and metastasis

Given the association of INAVA with more aggressive PTC, we next explored whether the function of INAVA in PTC could explain this association. We ectopically overexpressed INAVA in two PTC cell lines (TPC1 and K1) using empty vector as a control to determine its effect on the aggressive phenotype of the cells (Fig. 2a). As shown in Fig. 2b, c, in vitro cell invasion and migration assays showed that overexpression of INAVA significantly enhanced both the invasion and migration abilities of TPC1 and K1 cells. Scratch wound healing assay was performed to assess the effect of INAVA on cellular migration and the results showed that overexpression of INAVA significantly promoted wound closure in TPC1 and K1 cells (Fig. 2d). In an in vivo experimental metastasis assay, overexpression of INAVA promoted mouse lung colonization by tail vein-injected K1 cells (Fig. 2e and Additional file 1: Figure S1a).

Knockdown of INAVA inhibits PTC cells invasion, migration and metastasis

We next established pools of TPC1 and K1 cell lines with stable depletion of INAVA using retroviral-based shRNA vectors (Fig. 3a). As shown in Fig. 3b–e, Transwell assay with or without Matrigel coating showed that silencing of INAVA significantly decreased the invasiveness and migration of the TPC1 and K1 cell lines. Moreover, wound healing assay showed that knockdown of INAVA inhibited the migratory speed of TPC1 and K1 cells in comparison with that of the vector controls (Fig. 3f). In addition, knockdown of INAVA in K1 cells significantly decreased pulmonary metastatic nodule development (Fig. 3g and Additional file 1: Figure S1b). These data, together with results of Fig. 2, suggest that INAVA greatly contributes to the development of PTC invasion and metastasis.

MMP9 is the key molecule mediating INAVA-induced invasion and migration ability of PTC cells

To explore the molecular mechanisms by which INAVA regulates the invasion and metastasis ability of PTC cells, transcriptome resequencing was performed on INAVA-overexpressing TPC1 cells and vector control cells. Notably, many invasion/metastasis related genes were significantly increased in INAVA overexpressing TPC1 cells as compared with that in vector control (Fig. 4a). Importantly, among these genes, MMP9 was the most elevated gene in response to ectopic overexpression of INAVA. Next, real time RT-PCR assays were performed to confirm the results of deep sequencing analysis. As shown in Fig. 4b, the MMP9 mRNA expression levels were significantly increased and decreased in INAVA overexpressing and knockdown cell lines, respectively, suggesting that transcriptional efficiency of MMP9 is regulated by INAVA in PTC cells. The protein levels of MMP9 in indicated cells were in line with the changes of mRNA (Fig. 4c). As shown in Fig. 4d, the results of gelatin zymography showed that the secretion of MMP9 into culture medium was significantly increased in cells overexpressing INAVA and was significantly decreased in cells with INAVA knockdown. Moreover, knockdown of MMP9 using specific siRNAs in INAVA overexpressing TPC1 and K1 cells (Fig. 4e) suppressed the phenotype caused by INAVA overexpression (Fig. 4f). These results indicate that MMP9 plays a vital role in INAVA-induced cell invasion and migration.

FGF1 mediates the regulation of INAVA on MMP9

Given that MMP9 has been demonstrated to be regulated by FGF1 [19], together with that the results of deep sequencing analysis showed FGF1 was significantly upregulated in INAVA-overexpressing cells (Fig. 4a), we hypothesized that FGF1 was involved in the role of INAVA on regulation of MMP9. As expected, the mRNA and protein levels of FGF1 were elevated by overexpression of INAVA but were decreased by depletion of INAVA in PTC cells (Fig. 5a–d). Consistently, ELISA assays showed that INAVA-overexpressing cells secreted increased amount of FGF1, whereas INAVA silencing reduced the secretion of FGF1 (Fig. 5e). To further confirm the involvement of FGF1 in INAVA-mediated effects, the specific siRNAs were used to knockdown FGF1 in INAVA overexpressing cells. As shown in Fig. 5f, the upregulation of MMP9 induced by INAVA were inhibited by FGF1 silencing. As anticipated, invasive phenotype caused by INAVA overexpression was also suppressed by depletion of FGF1 (Fig. 5g). Taken together, these data indicate FGF1 play a vital role in INAVA-induced MMP9 expression and cell invasion.

INAVA expression correlates with FGF1 and MMP9 expression in primary PTC

To evaluate the correlations between INAVA expression and the levels of FGF1 and MMP9 in clinical specimens, IHC analyses were performed. As shown in Fig. 6a, b, 64.9% (37 cases) and 61.4% (35 cases) of samples with low INAVA expression (57 cases), respectively, exhibited low levels of FGF1 and MMP9, whereas 30.9% (17 cases) and 20.0% (11 cases) of samples with high INAVA expression (55 cases) showed low expression of FGF1 and MMP9, respectively (P < 0.05). Furthermore, we sorted patient cohort into low and high INAVA expression using RNAseq data mined from TCGA (INAVA low and high, n = 248 respectively). As shown in Fig. 6c, INAVA expression significantly correlated with the levels of FGF1 and MMP9 in PTC specimens. These results suggest that INAVA overexpression in PTC is associated with FGF1–MMP9 axis.

Discussion

The results of this study provided strong evidence supporting the oncogenic roles of INAVA in PTC. First, the expression of INAVA is significantly elevated in PTC specimens as compared with that in the adjacent non-tumorous thyroid specimens. Second, the increased expression of INAVA is associated with clinicopathologic parameters in PTC patients. Third, INAVA promotes the aggressive phenotypes of PTC cells in vitro and in vivo. Fourth, INAVA regulates FGF1–MMP9 axis, thereby contributing to aggressive phenotypes of PTC.

Although the expression of INAVA has been reported to be elevated in lung adenocarcinoma [15], its roles in cancer development and progression are largely unknown. While the molecular mechanism underlying the observed INAVA upregulation in PTC still need to be further investigated, our current data strongly showed that INAVA was significantly upregulated in PTC and was remarkably associated with cervical lymph metastasis by analyzing the TCGA data and our clinical cohorts. We therefore explored its pro-invasive and pro-metastatic functions in PTC cells by a series of in vitro and in vivo experiments. Our results showed that overexpression of INAVA led to enhancement of the invasive and metastatic capability of TPC1 and K1 cells. On contrary, INAVA silencing in PTC cells showed significantly inhibitory effects on invasion and metastasis. Our data demonstrate that INAVA plays an important role in the progression of malignant disease.

MMP9 degrades type IV collagen and plays important roles in various pathophysiological processes, such as wound healing, tumor invasiveness and progression [20, 21]. It has been demonstrated that MMP9 play important roles in the development and progression of thyroid cancer. For instance, the expression of MMP9 was significantly up-regulated in PTC and was correlated with clinicopathological parameters of the disease [22,23,24]. MMP9 plays an important role in astrocyte elevated gene-1 induced PTC progression and metastasis [25]. Further studies that aim at investigating the regulatory mechanisms underlying the MMP9 in PTC will improve our understanding of etiology of the disease. One of the key finding of the current study is represented by the identification of a new signaling cascade in PTC cells. Elevated INAVA upregulates the expression and secretion of FGF1, which subsequently results in upregulation of MMP9 and aggressive phenotypes of PTC cells. The data derived from current mechanistic study provide an explanation for the observed association between INAVA overexpression and cervical lymph metastasis in PTC. Of note, it would also be interesting to explore whether the same chain reaction also presents in other cancer types with INAVA overexpression.

Although most thyroid cancers of follicular epithelial derivation are well differentiated and well behaved, a small subset of thyroid cancers behave aggressively via genetic and epigenetic alterations [26,27,28]. PTC is known for its early spread to regional lymph nodes and growing evidence has demonstrated that central lymph node metastasis is adversely associated with survival [29, 30]. Distant metastasis occurs in only < 1% of thyroid cancer, but strongly associates with poor clinical outcomes [31,32,33]. Delineating the molecular aspects of the LN metastasis and distant metastasis in PTC will lead to a better understanding of the disease. Our finding provides new insights into the molecular mechanisms underlying the aggressive behavior of PTC by identifying INAVA as a novel promoter of tumor cell invasion and metastasis.

FGF1, an oncogene, has been demonstrated to regulate many cellular processes, including cell invasion, proliferation, and survival [34, 35]. FGF1 is upregulated in various tumors and is involved in progression of malignances [36,37,38]. The elevated expression of FGF1 has been found in PTC [39]. To delineate the regulatory mechanisms of deregulation of FGF1 in cancers is of great interest. Our data obtained in vitro using TPC1 and K1 cell lines showed that overexpression of INAVA enhanced the expression and secretion of FGF1, whereas INAVA silencing inhibited FGF1 expression and secretion. In addition, our clinical findings demonstrated a strong correlation between INAVA and FGF1 expression. Our data provide new insights into the current understanding on the regulatory networks that control the expression of FGF1 in malignant diseases.

FGF1 can be released into the extracellular environment via unclear mechanisms, by doing this, it acts as a paracrine or autocrine factor to activate specific cell surface receptors [40]. There are two possible sources of FGF1 within epithelial cancers, namely, the cancer cells or surrounding stromal cells. FGF1 may be secreted from either of these two sources and acts in a paracrine and/or autocrine manner [41]. Secreted FGF1 exerts its biological function via binding to, and activation of, fibroblast growth factor receptors (FGFRs) with intrinsic tyrosine kinase activity at the cellular surface and thereby triggering intracellular signaling cascades, including mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and phospholipase Cγ (PLCγ) signaling [19, 42, 43]. Of specific note, MAPK and NF-κB pathways are well known for regulating the expression of MMP9 [44, 45]. In current study, we found that INAVA increased the expression as well as the secretion of FGF1 in PTC cells. It is likely that MAPK and NF-κB pathways might be involved in INAVA-induced MMP9 expression. Another interesting issue need to be further investigated is whether the FGF1 secreted by the tumor cell may act in a paracrine manner to affect the surrounding stromal cells, which in turn facilitates the development and progression of PTC.

Conclusion

In summary, our data indicate that INAVA expression is elevated in PTC. Our data also show that INAVA expression is associated with aggressive phenotypes of PTC. We demonstrate that INAVA overexpression enhances invasion and metastasis via upregulation of MMP9. In addition, shRNA-mediated knockdown experiments further confirm the pro-invasive and pro-metastatic roles of INAVA in PTC. Furthermore, we show that the upregulation of MMP9 induced by INAVA is mediated by elevated FGF1. Taken as a whole, our data reveal a novel molecular mechanism that involves the aggressive phenotypes of PTC and may prove clinically useful for develo** a new therapeutic target for PTC invasion and metastasis.

Abbreviations

ALOX5:: arachidonate 5-lipoxygenase
BCA:: bicinchoninic acid assay
DMEM:: Dulbecco’s modified Eagle’s medium
ECACC:: European Collection of Cell Cultures
ECM:: extracellular matrix
ECL:: enhanced chemiluminescence
ELISA:: enzyme linked immunosorbent assay
FGF1:: fibroblast growth factor 1
GAPDH:: glyceraldehyde-3-phosphate dehydrogenase
GEO:: gene expression omnibus
HE:: hematoxylin and eosin
IHC:: immunohistochemistry
INAVA:: innate immunity activator
LN:: lymph node
NLN:: with no lymph node metastasis
MMPs:: matrix metalloproteinases
PTC:: papillary thyroid cancer
RT-PCR:: reverse transcription-polymerase chain reaction
SDS-PAGE:: sodium dodecyl sulfate–polyacrylamide gel electrophoresis
STR:: short tandem repeat
TCGA:: The Cancer Genome Atlas
TNM:: tumor-node-metastasis
WB:: western blotting

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Authors’ contributions

HG, YG, and LL planned and conducted experiments, analyzed the data and wrote the text. RY, WL, and HL conducted experiments and analyzed data. HX participated in its design and contributed to discuss the data and text. YL conceived of the study, and participated in its design and coordination and critical review of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We thank Prof. Haixia Guan (China Medical University, China) for TPC-1 cell line.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

RNAseqV2 data of 59 pairs of PTC tissues versus paired adjacent noncancerous thyroid tissues and 496 cases of PTC tissues were mined from The Cancer Genome Atlas (TCGA) (https://cancergenome.nih.gov/) using UCSC Xena (http://xena.ucsc.edu/getting-started/). The transcriptome resequencing data described herein have been deposited in the Gene Expression Omnibus (GEO) database and are accessible through GEO series Accession Number GSE100392.

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Not applicable.

Ethics approval and consent to participate

The use of clinical specimens and clinical data were reviewed and approved by the Institutional Research Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University. Written informed consent was obtained from all patients who participated in the study. Animal experiments were approved by the Institutional Animal Care and Use Committee of the First Affiliated Hospital, Sun Yat-sen University.

Funding

This research was supported by Grants from the National Natural Science Foundation of China (Nos. 81572624, 81572623, 81602347) and the Natural Science Foundation of Guangdong Province (No. 2016A030310169).

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Author information

Hongyu Guan, Yan Guo, and Liehua Liu contributed equally to this work

Authors and Affiliations

Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, China
Hongyu Guan, Yan Guo, Liehua Liu, Weiwei Liang, Hai Li, Haipeng **ao & Yanbing Li
Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Runyi Ye

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Hongyu Guan
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Yan Guo
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Liehua Liu
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Runyi Ye
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Hai Li
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Haipeng **ao
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Yanbing Li
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Correspondence to Yanbing Li.

Additional file

Additional file 1: Figure S1.

INAVA regulates PTC cell metastasis. Metastasis area was calculated using Image J software in HE stained sections.

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Guan, H., Guo, Y., Liu, L. et al. INAVA promotes aggressiveness of papillary thyroid cancer by upregulating MMP9 expression. Cell Biosci 8, 26 (2018). https://doi.org/10.1186/s13578-018-0224-4

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Received: 14 December 2017
Accepted: 30 March 2018
Published: 05 April 2018
DOI: https://doi.org/10.1186/s13578-018-0224-4

INAVA promotes aggressiveness of papillary thyroid cancer by upregulating MMP9 expression