Tumor microenvironment affects exogenous sodium/iodide symporter expression

Castillo-Rivera, Fabio; Ondo-Méndez, Alejandro; Guglielmi, Julien; Guigonis, Jean-Marie; Jing, Lun; Lindenthal, Sabine; González-Muñoz, Andrea; López, Diana M.; Cambien, Béatrice; Pourcher, Thierry

doi:10.1016/j.tranon.2020.100937

Cited by 14 publications

(12 citation statements)

References 81 publications

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“…Real-time PCR and western blotting both indicated that the expression of NIS was significant decreased under hypoxia in the PTC cells. Castillo-Rivera et al have provided evidence that hypoxia impaired NIS expression at the plasma membrane and iodide uptake within tumors, which findings were consistent with our results [31]. To demonstrate whether YAP was involved in the regulation of NIS expression, real-time PCR and western blotting were performed in PTC cells under hypoxia.…”

Section: Discussionsupporting

confidence: 92%

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression

Song¹,

Qiu²,

Wang³

et al. 2023

Int. J. Biol. Sci.

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Background:The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results:The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.

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Section: Discussionsupporting

confidence: 92%

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression

Song¹,

Qiu²,

Wang³

et al. 2023

Int. J. Biol. Sci.

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“…have demonstrated that the tumor microenvironment may play a role in regulation of NIS function and localization of NIS at the plasma membrane, thereby affecting the efficacy of NIS gene therapy approaches, which will have to be explored further in preclinical tumor models. 60 …”

Section: Discussionmentioning

confidence: 99%

Dual EGFR- and TfR-targeted gene transfer for sodium iodide symporter gene therapy of glioblastoma

Spellerberg

Benli-Hoppe

Kitzberger

et al. 2022

Molecular Therapy - Oncolytics

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“…Collectively, these reports suggest that HIF1-α is closely related to the pathophysiology of thyroid cancer, specifically in terms of tumor aggressiveness, progression, and metastasis with characteristics of dedifferentiation [ 48 , 52 ]. Several articles have reported the relationship between hypoxia and NIS expression [ 21 , 53 , 54 ]. Lan et al demonstrated that the overexpression of HIF1-α in thyroid cancers decreased NIS expression [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…Lan et al demonstrated that the overexpression of HIF1-α in thyroid cancers decreased NIS expression [ 53 ]. Moreover, another article reported that the tumor microenvironment, characterized by hypoxia and quiescence, could affect NIS expression and RAI uptake in exogenous NIS-expressing cancer cells [ 21 ]. Therefore, we speculated that 3D spheroid culture is hypoxic due to increased HIF-1α expression and that this phenomenon could influence the decline in thyroid-specific proteins and thyroid transcription factors.…”

Section: Discussionmentioning

confidence: 99%

“…A few studies have described the change in thyroid differentiation proteins using patient’s samples under the 3D culture condition [ 17 , 19 , 20 ], but no comparative study has discussed the change in differentiation characteristics of thyroid cancer cells between the 2D and 3D culture environments. A recent report emphasized that the tumor microenvironment, which involves hypoxia and quiescence, could affect the expression of the sodium iodide symporter (NIS) and membrane targeting after NIS-mediated RAI uptake in cancer cells expressing exogenous NIS [ 21 ]. Although the study involved non-thyroid cancer cells, it nevertheless suggested the possibility of a similar phenomenon in thyroid cancer by the same underlying mechanisms of impairment of NIS expression and translocation.…”

Section: Introductionmentioning

confidence: 99%

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Different Expression of Thyroid-Specific Proteins in Thyroid Cancer Cells between 2-Dimensional (2D) and 3-Dimensional (3D) Culture Environment

Gangadaran

Rajendran

et al. 2022

Cells

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The two-dimensional (2D) monolayer culture as a conventional method has been widely applied in molecular biology fields, but it has limited capability to recapitulate real cell environments, being prone to misinterpretation with poor prediction of in vivo behavior. Recently, the three-dimensional (3D) spheroid culture has been studied extensively. Spheroids are self-assembled cell aggregates that have biomimicry capabilities. The behavior of thyroid cancer under the 3D spheroid culture environment has been studied; however, there are no reports regarding differences in the degree of thyroid cancer cell differentiation under 2D and 3D culture conditions. This study investigated the expression of thyroid differentiation proteins related to iodide-metabolizing mechanisms in thyroid cancer cells under different culture conditions. Four thyroid cancer cell lines and one thyroid follicular epithelial cell line were grown in adherent 2D cell culture and 3D spheroid culture with agarose-coated plates. We observed changes in proliferation, hypoxia, extracellular matrix (ECM), cytoskeleton, thyroid-specific proteins, and thyroid transcription factors. All cell lines were successfully established in the spheroid following cell aggregation. Proliferation considerably decreased, while hypoxia-inducible factor 1-α(HIF1-α) was promoted in 3D spheroids; moreover, 3D spheroids with thyroid cancers showed diminished thyroid differentiation markers, but thyroid follicular epithelial cells revealed either a maintenance or weak decline of protein expression. We verified that the 3D spheroid culture environment can be similar to in vivo conditions because of its alterations in numerous cellular and functional activities, including morphology, cellular proliferation, viability, hypoxia, ECM, cytoskeleton, and thyroid differentiation, compared to the conventional 2D monolayer culture environment. An in vitro experimental study using 3D spheroid culture is ideal for the faster discovery of new drugs.

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Tumor microenvironment affects exogenous sodium/iodide symporter expression

Cited by 14 publications

References 81 publications

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression

HIF-1α/YAP Signaling Rewrites Glucose/Iodine Metabolism Program to Promote Papillary Thyroid Cancer Progression

Dual EGFR- and TfR-targeted gene transfer for sodium iodide symporter gene therapy of glioblastoma

Different Expression of Thyroid-Specific Proteins in Thyroid Cancer Cells between 2-Dimensional (2D) and 3-Dimensional (3D) Culture Environment

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