Stem Cell Cancer Research Articles

Predicting drug resistance.

A new approach helps examine the proportion of cancerous and healthy stem cells in patients with chronic myeloid leukemia and how this influences treatment outcomes.

Correction: Regua et al. TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers. Cancers 2021, 13, 2340

In the original publication [...]

Epigenetic and Immune Mechanisms Linking Breastfeeding to Lower Breast Cancer Rates.

This review shows how mammary stem cells (MaSCs) influence breast development, breastfeeding, and breast cancer risk. MaSCs, which can differentiate into various cell types, are vital for breast tissue health, but also disease development in breast tissue. Research shows that breastfeeding affects MaSCs, offering protection against breast cancer through various mechanisms. Hormonal changes such as increased prolactin concentration, oxytocin secretion, lower progesterone levels, and reduced exposure to estrogen during lactation promote apoptosis in potential cancer cells, boost immune surveillance, and modulate inflammation. Key findings reveal that pregnancy at an earlier age and extended breastfeeding reduce MaSC numbers, lowering cancer risk. Additionally, breastfeeding induces various epigenetic changes, such as DNA methylation and histone modification, which provide long-term protection against the development of cancer. Components of breast milk, like alpha-lactalbumin and lactoferrin, contribute by promoting cancer cell apoptosis and inhibiting tumor growth. The dual benefits of breastfeeding are reduced breast cancer risk for mothers and immunological advantages for infants. Multicenter epidemiology research has focused particular attention on longer breastfeeding duration associated with a reduced risk of triple-negative breast cancer. This review offers comprehensive evidence that breastfeeding protects against breast cancer through various biological, hormonal, and molecular mechanisms, showing the importance of promoting breastfeeding as a natural cancer prevention method. This article reviews the role of mammary stem cells in breast development, lactation, and breast cancer.

Inflammation-Associated Stem Cells in Gastrointestinal Cancers: Their Utility as Prognostic Biomarkers and Therapeutic Targets.

Stem cells are critical for the development and homeostasis of the gastrointestinal (GI) tract. Inflammatory molecules are known to regulate the activity of stem cells. A comprehensive review specifically describing the role of inflammatory molecules in the regulation of stem cells within the GI tract and in GI cancers (GICs) is not available. This review focuses on understanding the role of inflammatory molecules and stem cells in maintaining homeostasis of the GI tract. We further discuss how inflammatory conditions contribute to the transformation of stem cells into tumor-initiating cells. We also describe the molecular mechanisms of inflammation and stem cell-driven progression and metastasis of GICs. Furthermore, we report on studies describing the prognostic value of cancer stem cells and the clinical trials evaluating their therapeutic utility. This review provides a detailed overview on the role of inflammatory molecules and stem cells in maintaining GI tract homeostasis and their implications for GI-related malignancies.

PRMT1 promotes radiotherapy resistance in glioma stem cells by inhibiting ferroptosis.

The existence of glioma stem cells (GSCs) in cancer is related to glioma radiotherapy resistance. In this research, the effect of protein arginine methyltransferase 1 (PRMT1) on the radiosensitivity of glioma stem cell (GSC)-like cells, as well as its underlying mechanism, was investigated. GSCs-like cells were analyzed and identified by flow cytometry. The self-renewal capability was evaluated by sphere-forming assay. The PRMT1 expression level in glioblastoma were analyzed using the Gene Expression Profiling Interactive Analysis database. The mRNA and protein were scrutinized by RT-qPCR and western blot, respectively. The radiosensitivity was evaluated by clonogenic survival assay. Ferroptosis was evaluated by detecting the levels of reactive oxygen species, malondialdehyde, Fe2+, glutathione, and 4-hydroxynonenal. U87 and SHG44 cells with GSC-like phenotype (GSC-U87 and GSC-SHG44) displayed strong expression of CD133 and nestin versus the glioma cells. GSC-U87 and GSC-SHG44 possess the self-renewal capability. The level of PRMT1 was higher in glioblastoma tumor tissues than in the normal paracancer tissues. Knockdown of PRMT1 enhanced the radiotherapy sensitivity of GSCs-like cells, which wasevidenced by reduced survival fraction in GSC-U87 and GSC-SHG44 underwent sh-PRMT1 transfection. But, this effect was attenuated by Fer-1 (a ferroptosis inhibitor) treatment, accompanied by the abatement of ferroptosis. PRMT1 promoted radiotherapy resistance in GSCs-like cells by inhibiting ferroptosis.

Autofluorescent Cancer Stem Cells: Potential Biomarker to Predict Recurrence in Resected Colorectal Tumor.

Cancer stem cells (CSCs) in colorectal cancer (CRC) drive intratumoral heterogeneity and distant metastases. Previous research from our group showed that CSCs can be easily detected by autofluorescence (AF). The aim of the present study was to evaluate the potential role of AF CSCs as a prognostic biomarker for CRC relapse. Seventy-five freshly-resected tumors were analyzed, by flow cytometry. AF was categorized as high (H-AF) or low (L-AF), and results were correlated with histological features (grade of differentiation, presence of metastases in lymph nodes (LN), perivascular and lymphovascular invasion) and clinical variables (time to relapse and overall survival). Nineteen out of 75 (25.3%) patients experienced relapse (local or distant), 13 out of these 19 patients showed positive LNs and 6 patients had H-AF. Of note, 4 of them died before 5 years. While patients with H-AF CSCs percentages in the global population experienced 1.5 times increased relapse -HR 1.47, CI 95% (0.60 - 3.63), patients with H-AF CSC percentages and LN metastases had the highest risk of relapse; HR 7.92, p< 0.004, CI 95% (1.97 - 31.82). These data support AF as an accurate and feasible marker to identify CSCs in resected CRC. A strong statistical association between H-AF CSCs and the risk of relapse was observed, particularly in patients with positive LNs, suggesting that H-AF patients might benefit from adjuvant chemotherapy regimens and intensive surveillance due to their high propensity to experience disease recurrence.

Genetically engineered CD276-anchoring biomimetic nanovesicles target senescent escaped tumor cells to overcome chemoresistant and immunosuppressive breast cancer

Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.

The role of mesenchymal stem cells in cancer and prospects for their use in cancer therapeutics.

Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC-derived extracellular vesicles (MSCs-EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs-EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs-EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs-EVs in cancer treatment, along with the challenges they face.

Mechanism of DAPK1 for Regulating Cancer Stem Cells in Thyroid Cancer.

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine (Ser/Thr) protein kinase and is characteristically downregulated in metastatic cancer. Several studies showed that DAPK1 is involved in both the early and late stages of cancer. DAPK1 downregulation is elaborately controlled by epigenetic, transcriptional, posttranscriptional, and posttranslational processes. DAPK1 is known to regulate not only cancer cells but also stromal cells. Recent studies showed that DAPK1 was involved not only in tumor suppression but also in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in colon and thyroid cancers. CSCs are major factors in determining cancer aggressiveness in cancer metastasis and treatment prognosis by influencing EMT. However, the molecular mechanism involved in the regulation of cancer cells by DAPK1 remains unclear. In particular, little is known about the existence of CSCs and how they are regulated in papillary thyroid carcinoma (PTC) among thyroid cancers. In this review, we describe the molecular mechanism of CSC regulation by DAPK1 in PTC progression.

Combination of monensin and erlotinib synergistically inhibited the growth and cancer stem cell properties of triple-negative breast cancer by simultaneously inhibiting EGFR and PI3K signaling pathways.

Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are recognized as a highly challenging subset of cells, renowned for their heightened propensity for relapse and unfavorable prognosis. Monensin, an ionophoric antibiotic, has been reported to exhibit significant therapeutic efficacy against various cancers, especially CSCs. Erlotinib is classified as one of the EGFR-TKIs and has been previously identified as a promising therapeutic target for TNBC. Our research aims to assess the effectiveness of combination of monensin and erlotinib as a potential treatment strategy for TNBC. The combination of monensin and erlotinib was assessed for its potential anticancer activity through various in vitro assays, including cytotoxicity assay, colony formation assay, wound healing assay, transwell assay, mammosphere formation assay, and proportion of CSCs assay. Additionally, an in vivo study using tumor-bearing nude mice was conducted to evaluate the inhibitory effect of the monensin and erlotinib combination on tumor growth. The results indicated that combination of monensin with erlotinib synergistically inhibited cell proliferation, the migration rate, the invasion ability and decreased the CSCs proportion, and CSC markers SOX2 and CD133 in vivo and in vitro. Furthermore, the primary proteins involved in the signaling pathways of the EGFR/ERK and PI3K/AKT are simultaneously inhibited by the combination treatment of monensin and erlotinib in vivo and in vitro. The simultaneous inhibition of the EGFR/ERK and PI3K/AKT/mTOR signaling pathways by the combination of monensin and erlotinib exhibited a synergistic effect on suppressing tumor proliferation and cancer cell stemness in TNBC.

Targeted Treatment against Cancer Stem Cells in Colorectal Cancer.

The cancer stem cell (SC) theory proposes that a population of SCs serves as the driving force behind fundamental tumor processes, including metastasis, recurrence, and resistance to therapy. The standard of care for patients with stage III and high-risk stage II colorectal cancer (CRC) includes surgery and adjuvant chemotherapy. Fluoropyrimidines and their combination with oxaliplatin increased the cure rates, being able to eradicate the occult metastatic SC in a fraction of patients. The treatment for unresectable metastatic CRC is based on chemotherapy, antibodies to VEGF and EGFR, and tyrosine-kinase inhibitors. Immunotherapy is used in MSI-H tumors. Currently used drugs target dividing cells and, while often effective at debulking tumor mass, these agents have largely failed to cure metastatic disease. SCs are generated either due to genetic and epigenetic alterations in stem/progenitor cells or to the dedifferentiation of somatic cells where diverse signaling pathways such as Wnt/β-catenin, Hedgehog, Notch, TGF-β/SMAD, PI3K/Akt/mTOR, NF-κB, JAK/STAT, DNA damage response, and Hippo-YAP play a key role. Anti-neoplastic treatments could be improved by elimination of SCs, becoming an attractive target for the design of novel agents. Here, we present a review of clinical trials assessing the efficacy of targeted treatment focusing on these pathways in CRC.

Chemokine CXCL8 and its receptors as markers of colorectal cancer

BACKGROUND: The chemokine CXCL8 and its receptor are involved in the activation and transport of inflammatory mediators and regulate the proliferation and renewal of cancer stem cells in colon cancer. It is believed that CXC signaling may be associated with poor prognosis in colorectal cancer. AIM: To study the possibilities of using CXCL8-CXCR1/2 pathway indicators as markers in colorectal cancer. MATERIAL AND METHODS: Isolation of ribonucleic acid (RNA) from histological sections of tumors obtained intraoperatively from 59 patients diagnosed with colorectal cancer was carried out using magnetic particles, and quantitative polymerase chain reaction in real time was performed. Calculation of the normalized expression of the CXCL8 and CXCR1 genes relative to the referee gene was done using special software. Statistical data processing was performed using Statistica 3.0, BioStat v. 7.1 programs. Comparisons of characteristics were performed using the Mann–Whitney U test. Cox and Kaplan–Meier criteria were used to analyze overall and disease-free survival. RESULTS: The expression of CXCL8 in intestinal adenocarcinoma cells with low differentiation [Me (Q1–Q3) — 8.770 (1.127–1.114)] was significantly higher than in the groups of moderately and well differentiated tumors (p=0.004 and p=0.012, respectively); and in tumor tissue refractory to chemotherapy, it was significantly higher [4.374 (2.052–7.045)] compared to resistant [2.200 (1.388–5.037); p=0.008] and sensitive [1.624 (0.739–2.586); p=0.042]. The level of CXCR1 messenger RNA in tumor tissue was increased in the presence of BRAF mutation [3.645 (0.801–1.090); p=0.009] and low tumor differentiation [6.965 (3.938–12.225); p=0.002], as well as in tumor tissue refractory to FOLFOX/XELOX chemotherapy [46.224 (27.580–83.570); p=0.0009]. CONCLUSION: Expression of components of the CXCL8-CXCR1/2 signaling pathway in tumor tissue may be a marker of sensitivity to FOLFOX/XELOX chemotherapy in colorectal cancer.

Role of epithelial-to-mesenchymal transition and cancer stem cells in colorectal cancer

Role of epithelial-to-mesenchymal transition and cancer stem cells in colorectal cancer

Cancer Stem Cells in Breast Cancer

Breast cancer represents a real public health problem in Morocco with one of the highest rates of mortality. Cancer stem cells are a small subset of cells found in many types of malignancies, including breast cancer, they have a crucial role in carcinogenesis, progression, recurrences and therapeutic resistance. Our study aims to understand the characteristics of breast cancer stem cells that could explain the aggressive behavior of certain tumors, with an emphasis on CD326, as a biomarker for BCSC, hoping for new targeted therapies in the future.

The Impact of Cancer Stem Cells in Colorectal Cancer.

Despite incessant research, colorectal cancer (CRC) is still one of the most common causes of fatality in both men and women worldwide. Over time, advancements in medical treatments have notably enhanced the survival rates of patients with colorectal cancer. Managing metastatic CRC involves a complex tradeoff between the potential benefits and adverse effects of treatment, considering factors like disease progression, treatment toxicity, drug resistance, and the overall impact on the patient's quality of life. An increasing body of evidence highlights the significance of the cancer stem cell (CSC) concept, proposing that CSCs occupy a central role in triggering cancer. CSCs have been a focal point of extensive research in a variety of cancer types, including CRC. Colorectal cancer stem cells (CCSCs) play a crucial role in tumor initiation, metastasis, and therapy resistance, making them potential treatment targets. Various methods exist for isolating CCSCs, and understanding the mechanisms of drug resistance associated with them is crucial. This paper offers an overview of the current body of research pertaining to the comprehension of CSCs in colorectal cancer.

Transcription factor ZIC2 regulates the tumorigenic phenotypes associated with both bulk and cancer stem cells in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in North America. Current therapeutic regimens are ineffective against advanced EOC. A better understanding of the molecular mechanisms that regulate the biology of EOC will be a critical step toward developing more efficacious therapies against EOC. Herein, we demonstrate that elevated expression of transcription factor ZIC2 was associated with lower survival of EOC patients. Knockout of endogenous ZIC2 in EOC cells attenuated the tumorigenic phenotypes associated with both bulk and cancer stem cells in vitro and in vivo, indicating a pro-tumorigenic role of ZIC2 in EOC. On the other hand, however, overexpression of ZIC2 in EOC cells that do not express endogenous ZIC2 promoted cell migration and sphere formation, but inhibited cell growth and colony formation in vitro and tumor growth in vivo, indicating that the role for ZIC2 in EOC is context dependent. Our transcriptomic analysis showed that ZIC2-regulated genes were involved in multiple biological processes and signaling pathways associated with tumor progression. In conclusion, our findings reveal a context-dependent role for ZIC2 in regulating tumorigenic phenotypes in EOC, providing evidence that ZIC2 can be a potential therapeutic target for EOCs that express a high level of ZIC2.

Abstract 266: The effects of retinoid agents and retinoic acid receptor genotype on proliferation, differentiation, and stem cells in colorectal cancer

Abstract Understanding how to therapeutically target colonic stem cells (SCs) is important because SC overpopulation drives CRC growth and development. Our goal is to therapeutically sensitize cancer SCs (CSCs) to the differentiation-inducing effects of retinoid agents. We previously found that ALDH specifically marks normal and malignant colonic SCs. We also found that retinoic acid (RA) receptors and other RA signaling components are selectively expressed in ALDH+ SCs, indicating that RA signaling occurs through ALDH+ SCs. Because all-trans retinoic acid (ATRA) is a highly effective treatment for acute promyelocytic leukemia, which is caused by a genetic translocation involving retinoic acid receptor alpha (RARA), we conjecture that the response of RA agents may be effective against solid tumors depending on their pathway genotype. Our bioinformatics analysis on mutations and overexpression of RA signaling component genes in CRC showed that most of the RA pathway genes are altered in human CRCs. Therefore, we hypothesize that the ability of retinoid agents and retinoid metabolism blocking agents to induce differentiation of CSCs depends on the RA pathway genotype of CRC cells.Testing the effect of various retinoid drugs on cell proliferation shows that RA pathway genotype affects the response of RA agents in CRC cell lines. HCT116 and SW480 CRC cell lines, which have RA receptor mutations, displayed resistance to ATRA. In contrast, HT29 CRC cells that have wild-type RA receptors are sensitive to ATRA. All three cell lines however showed similar dose responses to the ATRA metabolizing enzyme, CYP26A1 inhibitor Liarozole. This finding indicates that regardless of RA receptor mutations, inhibition of ATRA metabolism can increase intracellular RA levels in a similar manner on all three cell lines to induce anti-proliferative effects. We used CRISPR-Cas9 gene editing to knock out the RARA gene in HT29 cells and evaluated its response to ATRA compared to HT29 cells. The RARA knockout derived lines showed reduced sensitivity to ATRA treatment and a slower rate of cell division compared to HT29 control cells. Additionally, Nanostring mRNA profiling analysis shows that ATRA treatment of HT29 cells increases expression of RARA, CYP26A1, and KRT20 (differentiation marker); and decreased decreases expression of CSC markers LGR5 and ALDH1A1. Altogether, these findings indicate that upregulated RA signaling can reduce cell proliferation, increase differentiation, and decrease CSC numbers in CRCs. Overall, our findings indicate that colon SCs are regulated by RA signaling mechanisms and dysregulation of RA signaling contributes to the SC overpopulation that drives CRC growth. Thus, therapeutically sensitizing CSCs to differentiation-inducing effects of retinoid agents should provide insight into designing new SC-targeted therapies for CRC. Citation Format: Victoria O. Hunsu, Caroline O. Facey, Bruce M. Boman. The effects of retinoid agents and retinoic acid receptor genotype on proliferation, differentiation, and stem cells in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 266.

Abstract 4654: Targeting poly-resistant stem cells in high-grade serous ovarian cancer via synthetic lethal drugs

Abstract High-grade serous ovarian cancer (HGSOC) is remarkably responsive to chemotherapy and yet recurs at high rates as resistant disease. Using novel technology that selects for rare clonogenic cells which recapitulate HGSOC in immunodeficient mice, we have identified, in therapy-naive HGSOC, a minor population of clones that are intrinsically resistant to paclitaxel/carboplatin as well as to a broad spectrum of oncology drugs. These intrinsic "polyresistant" cells are a common, albeit minor, component of clonogenic cells in all therapy-naive tumors analyzed. Importantly, the polyresistant clonogenic cells share a gene expression signature distinct from the majority of clonogenic cells that are exquisitely sensitive to paclitaxel/carboplatin, and this gene signature of polyresistant cells extends to all polyresistant clones within a patient and across HGSOC cases. We have exploited these polyresistant clones to perform high-throughput screening of small molecule "bioactive" libraries to identify compounds that circumvent this resistance. While single agent "hits" were obtained, these showed minimal therapeutic windows relative to normal stem cells of the liver and gastrointestinal tract. Adaptations of synthetic lethal strategies have yielded lead drug combinations that eliminate polyresistant clones from all four cases tested at low nanomolar concentrations in vitro. We have improved these combinations via the synthesis of new chemical entities that show potent effects against both subcutaneous and peritoneal tumor models in immunodeficient mice derived from polyresistant HGSOC clones. Clonogenic analyses of these treated and untreated xenografts support the notion that these drug combinations are targeting the stem cell populations within these tumors. We anticipate that these drug combinations will assist in preventing or treating recurrent HGSOC. Citation Format: Wa Xian, Frank McKeon, Christopher Crum, Jaffer Ajani, Peter Davies, Matthew Vincent, William Bachovchin, Hung-Sen Lai, Shuang Pan, Melina Khorrami, Melika khorrami, Raul caballero Montes, Paria Mosaffa, Ashley Hoffman, Amber Su. Targeting poly-resistant stem cells in high-grade serous ovarian cancer via synthetic lethal drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4654.

Targeting metastasis-initiating cancer stem cells in gastric cancer with leukaemia inhibitory factor

Gastric cancer’s (GC) bad prognosis is usually associated with metastatic spread. Invasive cancer stem cells (CSC) are considered to be the seed of GC metastasis and not all CSCs are able to initiate metastasis. Targeting these aggressive metastasis-initiating CSC (MIC) is thus vital. Leukaemia inhibitory factor (LIF) is hereby used to target Hippo pathway oncogenic members, found to be induced in GC and associated with CSC features. LIF-treated GC cell lines, patient-derived xenograft (PDX) cells and/or CSC tumourspheres underwent transcriptomics, laser microdissection-associated proteomics, 2D and 3D invasion assays and in vivo xenograft in mice blood circulation. LIFR expression was analysed on tissue microarrays from GC patients and in silico from public databases. LIF-treated cells, especially CSC, presented decreased epithelial to mesenchymal transition (EMT) phenotype and invasion capacity in vitro, and lower metastasis initiation ability in vivo. These effects involved both the Hippo and Jak/Stat pathways. Finally, GC’s high LIFR expression was associated with better clinical outcomes in patients. LIF treatment could thus represent a targeted anti-CSC strategy to fight against metastatic GC, and LIFR detection in primary tumours could constitute a potential new prognosis marker in this disease.

Role of sodium/iodide symporter overexpression in inhibiting thyroid cancer cell invasion and stem cell maintenance by inhibiting the β-catenin/LEF-1 pathway

BackgroundIn thyroid cancers, a reduction in the expression of the sodium/iodide symporter (NIS) is observed concomitant with a diminution in cancer cell differentiation. The β-catenin/LEF-1 pathway emerges as a crucial regulatory pathway influencing the functional expression of NIS in human thyroid cancer cells. Further research is required to comprehensively elucidate the role of NIS overexpression in impeding the progression of thyroid cancer cells. MethodsHuman papillary thyroid carcinoma (PTC) cell lines, specifically PTC-1 and KTC-1, were subjected to Scratch and Transwell assays, colony formation, and tumor sphere formation tests to investigate invasion and migration, focusing on the impact of NIS overexpression. The assessment involved the use of western blot to analyze the expression levels of β-catenin, NIS, CD133, SRY-related HMG box2 (Sox2), lymphoid enhancer-binding factor 1 (LEF-1), NANOG, octamer-binding transcription factor 4 (Oct4), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), and epithelial cellular adhesion molecule (EpCAM). Statistical analysis was conducted using SPSS version 20.0, and the graphs were developed using GraphPad Prism 7 (GraphPad Software, Inc.). ResultsOur observations revealed that Nthy-ori-3-1 cell lines exhibited notably higher average expression levels of NIS, yet significantly lower levels of LEF-1 and β-catenin compared to PTC-1 and KTC-1 cell lines. Furthermore, the overexpression of β-catenin resulted in reduced binding of LEF-1 to NIF promotion but concurrently increased the expression of NIS. The downregulation of NIS markedly enhanced the expression of ALDH1A1, CD133, OCT4, Nanog, SOX2, and EpCam—all of which are targets within the Wnt/β-catenin signaling pathway. Conversely, the upregulation of NIS suppressed the expression of these proteins. Moreover, cells treated with β-catenin activators demonstrated an increased capability to form more spheroids and displayed heightened aggressiveness. Conversely, the NIS overexpression (OE) group exhibited suppressed abilities in invasion and colony formation. ConclusionThyroid cancer cells exhibit diminished expression of NIS, and the invasion and maintenance of stem cells in thyroid cancer cells were hindered by NIS OE through the inhibition of the β-catenin/LEF-1 pathway. Further research is warranted to comprehensively assess this outcome, which holds promise as a potential targeted treatment for thyroid cancer.