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16 pages, 36931 KiB

Open AccessArticle

Interaction of MRPL9 and GGCT Promotes Cell Proliferation and Migration by Activating the MAPK/ERK Pathway in Papillary Thyroid Cancer

by Hui-Min Zhang, Zi-Yi Li, Zhou-Tong Dai, Jun Wang, Le-Wei Li, Qi-Bei Zong, Jia-Peng Li, Tong-Cun Zhang and Xing-Hua Liao

Int. J. Mol. Sci. 2022, 23(19), 11989; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911989 - 09 Oct 2022

Cited by 5 | Viewed by 1813

Abstract

Thyroid cancer remains the most common endocrine malignancy worldwide, and its incidence has steadily increased over the past four years. Papillary Thyroid Cancer (PTC) is the most common differentiated thyroid cancer, accounting for 80–85% of all thyroid cancers. Mitochondrial proteins (MRPs) are an [...] Read more.

Thyroid cancer remains the most common endocrine malignancy worldwide, and its incidence has steadily increased over the past four years. Papillary Thyroid Cancer (PTC) is the most common differentiated thyroid cancer, accounting for 80–85% of all thyroid cancers. Mitochondrial proteins (MRPs) are an important part of the structural and functional integrity of the mitochondrial ribosomal complex. It has been reported that MRPL9 is highly expressed in liver cancer and promotes cell proliferation and migration, but it has not been reported in PTC. In the present study we found that MRPL9 was highly expressed in PTC tissues and cell lines, and lentivirus-mediated overexpression of MRPL9 promoted the proliferation and migration ability of PTC cells, whereas knockdown of MRPL9 had the opposite effect. The interaction between MRPL9 and GGCT (γ-glutamylcyclotransferase) was found by immunofluorescence and co-immunoprecipitation experiments (Co-IP). In addition, GGCT is highly expressed in PTC tissues and cell lines, and knockdown of GGCT/MRPL9 in vivo inhibited the growth of subcutaneous xenografts in nude mice and inhibited the formation of lung metastases. Mechanistically, we found that knockdown of GGCT/MRPL9 inhibited the MAPK/ERK signaling pathway. In conclusion, our study found that the interaction of GGCT and MRPL9 modulates the MAPK/ERK pathway, affecting the proliferation and migration of PTC cells. Therefore, GGCT/MRPL9 may serve as a potential biomarker for PTC monitoring and PTC treatment. Full article

(This article belongs to the Special Issue Thyroid Disease and Thyroid Cancer)

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18 pages, 3111 KiB

Open AccessArticle

Potential Therapeutic Agents against Paclitaxel—And Sorafenib-Resistant Papillary Thyroid Carcinoma

by Seok-Mo Kim, Keunwan Park, Jin Hong Lim, Hyeok Jun Yun, Sang Yong Kim, Kyung Hwa Choi, Chan Wung Kim, Jae Ha Lee, Raymond Weicker, Cheol-Ho Pan and Ki Cheong Park

Int. J. Mol. Sci. 2022, 23(18), 10378; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810378 - 08 Sep 2022

Cited by 3 | Viewed by 1729

Abstract

Thyroid carcinoma, a disease in which malignant cells form in the thyroid tissue, is the most common endocrine carcinoma, with papillary thyroid carcinoma (PTC) accounting for nearly 80% of total thyroid carcinoma cases. However, the management of metastatic or recurrent therapy-refractory PTC is [...] Read more.

Thyroid carcinoma, a disease in which malignant cells form in the thyroid tissue, is the most common endocrine carcinoma, with papillary thyroid carcinoma (PTC) accounting for nearly 80% of total thyroid carcinoma cases. However, the management of metastatic or recurrent therapy-refractory PTC is challenging and requires complex carcinoma therapy. In this study, we proposed a new clinical approach for the treatment of therapy-refractory PTC. We identified sarco/endoplasmic reticulum calcium ATPase (SERCA) as an essential factor for the survival of PTC cells refractory to the treatment with paclitaxel or sorafenib. We validated its use as a potential target for developing drugs against resistant PTC, by using patient-derived paclitaxel- or sorafenib-resistant PTC cells. We further discovered novel SERCA inhibitors, candidates 7 and 13, using the evolutionary chemical binding similarity method. These novel SERCA inhibitors determined a substantial reduction of tumors in a patient-derived xenograft tumor model developed using paclitaxel- or sorafenib-resistant PTC cells. These results could provide a basis for clinically meaningful progress in the treatment of refractory PTC by identifying a novel therapeutic strategy: using a combination therapy between sorafenib or paclitaxel and specific SERCA inhibitors for effectively and selectively targeting extremely malignant cells such as antineoplastic-resistant and carcinoma stem-like cells. Full article

(This article belongs to the Special Issue Thyroid Disease and Thyroid Cancer)

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8 pages, 2814 KiB

Open AccessArticle

PAPPA Expression in Indeterminate Thyroid Nodules as Screening Test to Select Patients for Molecular Testing

by Carlotta Marzocchi, Silvia Cantara, Alfonso Sagnella and Maria Grazia Castagna

Int. J. Mol. Sci. 2022, 23(9), 4648; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094648 - 22 Apr 2022

Cited by 1 | Viewed by 1513

Abstract

Pregnancy-associated plasma protein A (PAPPA) acts as an oncogene, and its expression is increased in multiple malignancies, including thyroid cancer. Molecular tests represent a useful tool in the management of indeterminate thyroid nodules; however, they are not conducted in all centers, and they [...] Read more.

Pregnancy-associated plasma protein A (PAPPA) acts as an oncogene, and its expression is increased in multiple malignancies, including thyroid cancer. Molecular tests represent a useful tool in the management of indeterminate thyroid nodules; however, they are not conducted in all centers, and they contribute to increase the per-patient cost of nodule evaluation. In this study, we examined whether PAPPA expression could represent a promising new screening test in the management of indeterminate thyroid nodules. Toward this aim, PAPPA expression was evaluated in 107 fine needle aspiration cytologies (FNAC) belonging to Bethesda III–IV categories that had been sent to molecular biology to discriminate the nature of the nodules. We found that the PAPPA expression increased and showed an elevated sensitivity (97.14%) and negative predictive value (98%) in indeterminate cytological samples positive for mutations. The enhanced expression was not linked to a specific oncogene. Our findings demonstrated that assessing the PAPPA expression in indeterminate thyroid cytologies could represent a useful screening tool to select all patients that effectively need to be sent to molecular testing, thereby, leading to a potential cost reduction in the management of patients. Full article

(This article belongs to the Special Issue Thyroid Disease and Thyroid Cancer)

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19 pages, 4156 KiB

Open AccessArticle

Extracellular Vesicles as Signal Carriers in Malignant Thyroid Tumors?

by Małgorzata Grzanka, Anna Stachurska-Skrodzka, Anna Adamiok-Ostrowska, Ewa Gajda and Barbara Czarnocka

Int. J. Mol. Sci. 2022, 23(6), 3262; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063262 - 17 Mar 2022

Cited by 2 | Viewed by 1944

Abstract

Extracellular vesicles (EVs) are small, membranous structures involved in intercellular communication. Here, we analyzed the effects of thyroid cancer-derived EVs on the properties of normal thyroid cells and cells contributing to the tumor microenvironment. EVs isolated from thyroid cancer cell lines (CGTH, FTC-133, [...] Read more.

Extracellular vesicles (EVs) are small, membranous structures involved in intercellular communication. Here, we analyzed the effects of thyroid cancer-derived EVs on the properties of normal thyroid cells and cells contributing to the tumor microenvironment. EVs isolated from thyroid cancer cell lines (CGTH, FTC-133, 8505c, TPC-1 and BcPAP) were used for treatment of normal thyroid cells (NTHY), as well as monocytes and endothelial cells (HUVEC). EVs’ size/number were analyzed by flow cytometry and confocal microscopy. Gene expression, protein level and localization were investigated by qRT-PCR, WB and ICC/IF, respectively. Proliferation, migration and tube formation were analyzed. When compared with NTHY, CGTH and BcPAP secreted significantly more EVs. Treatment of NTHY with cancer-derived EVs changed the expression of tetraspanin genes, but did not affect proliferation and migration. Cancer-derived EVs suppressed tube formation by endothelial cells and did not affect the phagocytic index of monocytes. The number of 6 μm size fraction of cancer-derived EVs correlated negatively with the CD63 and CD81 expression in NTHY cells, as well as positively with angiogenesis in vitro. Thyroid cancer-derived EVs can affect the expression of tetraspanins in normal thyroid cells. It is possible that 6 μm EVs contribute to the regulation of NTHY gene expression and angiogenesis. Full article

(This article belongs to the Special Issue Thyroid Disease and Thyroid Cancer)

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11 pages, 803 KiB

Open AccessArticle

Modifier Role of Common RET Variants in Sporadic Medullary Thyroid Carcinoma

by Anna Skalniak, Małgorzata Trofimiuk-Müldner, Elwira Przybylik-Mazurek and Alicja Hubalewska-Dydejczyk

Int. J. Mol. Sci. 2021, 22(21), 11794; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111794 - 30 Oct 2021

Cited by 1 | Viewed by 1681

Abstract

Background: Although the disease-causing effect of pathogenic variants in the gene RET has been unambiguously identified, there is a lack of consensus regarding the possible impact of common variants in this gene. Our study aimed to test whether variants in exons 10, 11, [...] Read more.

Background: Although the disease-causing effect of pathogenic variants in the gene RET has been unambiguously identified, there is a lack of consensus regarding the possible impact of common variants in this gene. Our study aimed to test whether variants in exons 10, 11, and 13–16 that are commonly detected during routine diagnostic testing might have any modifying effect on MTC. Methods: In sporadic MTC patients with no pathogenic variants but with or without common variants in RET, the following variants were evaluated: rs1799939 (p.G691S), rs1800861 (p.L769=), rs1800862 (p.S836=), rs2472737 in intron 14, and rs1800863 (p.S904=). Results: After Bonferroni correction, none of the variants were statistically significantly associated with disease outcome when analysed independently. The MTC group was divided into three genetically different clusters by unsupervised k-means clustering. Those clusters differed significantly in the age at diagnosis. A trend towards the association of given clusters with metabolic disorders and with remission state was identified. Conclusions: Although common variants in RET are not responsible for the risk of MTC, their analysis might turn out useful in the prediction of a patient’s clinical outcome. Importantly, this analysis would come with no additional cost in laboratories with a diagnostic procedure based on exon sequencing. Full article

(This article belongs to the Special Issue Thyroid Disease and Thyroid Cancer)

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17 pages, 2986 KiB

Open AccessArticle

Regulatory B Cells Involvement in Autoimmune Phenomena Occurring in Pediatric Graves’ Disease Patients

by Kamil Grubczak, Aleksandra Starosz, Karolina Stożek, Filip Bossowski, Marcin Moniuszko and Artur Bossowski

Int. J. Mol. Sci. 2021, 22(20), 10926; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010926 - 10 Oct 2021

Cited by 3 | Viewed by 2297

Abstract

Graves’s disease is the most common type of autoimmune hyperthyroidism. Numerous studies indicate different factors contributing to the onset of the disease. Despite years of research, the exact pathomechanism of Graves’ disease still remains unresolved, especially in the context of immune response. B [...] Read more.

Graves’s disease is the most common type of autoimmune hyperthyroidism. Numerous studies indicate different factors contributing to the onset of the disease. Despite years of research, the exact pathomechanism of Graves’ disease still remains unresolved, especially in the context of immune response. B cells can play a dual role in autoimmune reactions, on the one hand, as a source of autoantibody mainly targeted in the thyroid hormone receptor (TSHR) and, on the other, by suppressing the activity of proinflammatory cells (as regulatory B cells). To date, data on the contribution of Bregs in Graves’ pathomechanism, especially in children, are scarce. Here, we investigated the frequencies of Bregs before and during a methimazole therapy approach. We reported higher Foxp3+ and IL-10+ Breg levels with CD38- phenotype and reduced numbers of CD38 + Foxp3 + IL-10+ in pediatric Graves’ patients. In addition, selected Breg subsets were found to correlate with TSH and TRAb levels significantly. Noteworthy, certain subpopulations of Bregs were demonstrated as prognostic factors for methimazole therapy outcome. Our data demonstrate the crucial role of Bregs and their potential use as a biomarker in Graves’ disease management. Full article

(This article belongs to the Special Issue Thyroid Disease and Thyroid Cancer)

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21 pages, 4268 KiB

Open AccessArticle

Association of miR-499 Polymorphism and Its Regulatory Networks with Hashimoto Thyroiditis Susceptibility: A Population-Based Case-Control Study

by Farhad Tabasi, Vahed Hasanpour, Shamim Sarhadi, Mahmoud Ali Kaykhaei, Pouria Pourzand, Mehrdad Heravi, Ahmad Alinaghi Langari, Gholamreza Bahari, Mohsen Taheri, Mohammad Hashemi and Saeid Ghavami

Int. J. Mol. Sci. 2021, 22(18), 10094; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810094 - 18 Sep 2021

Cited by 4 | Viewed by 2794

Abstract

Hashimoto thyroiditis (HT) is a common autoimmune disorder with a strong genetic background. Several genetic factors have been suggested, yet numerous genetic contributors remain to be fully understood in HT pathogenesis. MicroRNAs (miRs) are gene expression regulators critically involved in biological processes, of [...] Read more.

Hashimoto thyroiditis (HT) is a common autoimmune disorder with a strong genetic background. Several genetic factors have been suggested, yet numerous genetic contributors remain to be fully understood in HT pathogenesis. MicroRNAs (miRs) are gene expression regulators critically involved in biological processes, of which polymorphisms can alter their function, leading to pathologic conditions, including autoimmune diseases. We examined whether miR-499 rs3746444 polymorphism is associated with susceptibility to HT in an Iranian subpopulation. Furthermore, we investigated the potential interacting regulatory network of the miR-499. This case-control study included 150 HT patients and 152 healthy subjects. Genotyping of rs3746444 was performed by the PCR-RFLP method. Also, target genomic sites of the polymorphism were predicted using bioinformatics. Our results showed that miR-499 rs3746444 was positively associated with HT risk in heterozygous (OR = 3.32, 95%CI = 2.00–5.53, p < 0.001, CT vs. TT), homozygous (OR = 2.81, 95%CI = 1.30–6.10, p = 0.014, CC vs. TT), dominant (OR = 3.22, 95%CI = 1.97–5.25, p < 0.001, CT + CC vs. TT), overdominant (OR = 2.57, 95%CI = 1.62–4.09, p < 0.001, CC + TT vs. CT), and allelic (OR = 1.92, 95%CI = 1.37–2.69, p < 0.001, C vs. T) models. Mapping predicted target genes of miR-499 on tissue-specific-, co-expression-, and miR-TF networks indicated that main hub-driver nodes are implicated in regulating immune system functions, including immunorecognition and complement activity. We demonstrated that miR-499 rs3746444 is linked to HT susceptibility in our population. However, predicted regulatory networks revealed that this polymorphism is contributing to the regulation of immune system pathways. Full article

(This article belongs to the Special Issue Thyroid Disease and Thyroid Cancer)

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33 pages, 1068 KiB

Open AccessReview

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

by Maciej Ratajczak, Damian Gaweł and Marlena Godlewska

Int. J. Mol. Sci. 2021, 22(21), 11829; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111829 - 31 Oct 2021

Cited by 30 | Viewed by 3160

Abstract

Thyroid cancers (TCs) are the most common tumors of the endocrine system and a constant rise in the number of TC cases has been observed for the past few decades. TCs are one of the most frequent tumors in younger adults, especially in [...] Read more.

Thyroid cancers (TCs) are the most common tumors of the endocrine system and a constant rise in the number of TC cases has been observed for the past few decades. TCs are one of the most frequent tumors in younger adults, especially in women, therefore early diagnosis and effective therapy are especially important. Ultrasonography examination followed by fine needle biopsy have become the gold standard for diagnosis of TCs, as these strategies allow for early-stage detection and aid accurate qualification for further procedures, including surgical treatment. Despite all the advancements in detection and treatment of TCs, constant mortality levels are still observed. Therefore, a novel generation line of targeted treatment strategies is being developed, including personalized therapies with kinase inhibitors. Recent molecular studies on TCs demonstrate that kinase inhibitor-based therapies might be considered as the most promising. In the past decade, new kinase inhibitors with different mechanisms of action have been reported and approved for clinical trials. This review presents an up-to-date picture of new approaches and challenges of inhibitor-based therapies in treatment of TCs, focusing on the latest findings reported over the past two years. Full article

(This article belongs to the Special Issue Thyroid Disease and Thyroid Cancer)

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