Cancer Stem Cell-like Properties Research Articles

Roles of Chemokine Axes in Breast Cancer.

Chemokines bind to specific chemokine receptors, known as cell surface G protein-coupled receptors, constructing chemokine axes which lead to cell migration and invasion in developmental stage, pathophysiological process, and immune reactions. The chemokine axes in the tumor microenvironment are involved in tumor growth, angiogenesis, cancer stem-like cell properties, metastasis, and chemoresistance, modifying tumor immune contexture and cancer progression. Clinical features, including tumor state, grade, lymph node metastasis, and cancer subtypes, are related to the specific chemokine axes, which play a significant role in immune contexture and cell to cell interaction in the tumor microenvironment, followed by altered cancer prognosis and overall survival. The present review summarizes the role of chemokine axes in breast cancer, based on data obtained from cell line and animal models and human tumor samples. This review provides information that understand the important roles of each chemokine axis in breast cancer, probably offering a clue of adjuvant therapeutic options to improve the quality of life and survival for patients with breast cancer.

CircUBA2 promotes the cancer stem cell-like properties of gastric cancer through upregulating STC1 via sponging miR-144-5p

BackgroundCancer stem cells (CSCs) are critical factors that limit the effectiveness of gastric cancer (GC) therapy. Circular RNAs (circRNAs) are confirmed as important regulators of many cancers. However, their role in regulating CSC-like properties of GC remains largely unknown. Our study aimed to investigate the role of circUBA2 in CSC maintenance and the underlying mechanisms.MethodsWe identified circUBA2 as an upregulated gene using circRNA microarray analysis. qRT-PCR was used to examine the circUBA2 levels in normal and GC tissues. In vitro and in vivo functional assays were performed to validate the role of circUBA2 in proliferation, migration, metastasis and CSC-like properties of GC cell. The relationship between circUBA2, miR-144-5p and STC1 was characterised using bioinformatics analysis, a dual fluorescence reporter system, FISH, and RIP assays.ResultsCircUBA2 expression was significantly increased in GC tissues, and patients with GC with high circUBA2 expression had a poor prognosis. CircUBA2 enhances CSC-like properties of GC, thereby promoting cell proliferation, migration, and metastasis. Mechanistically, circUBA2 promoted GC malignancy and CSC-like properties by acting as a sponge for miR-144-5p to upregulate STC1 expression and further activate the IL-6/JAK2/STAT3 signaling pathway. More importantly, the ability of circUBA2 to enhance CSC-like properties was inhibited by tocilizumab, a humanised Interleukin-6 receptor (IL-6R) antibody. Thus, circUBA2 knockdown and tocilizumab synergistically inhibited CSC-like properties.ConclusionsOur study demonstrated the critical role of circUBA2 in regulating CSC-like properties in GC. CircUBA2 may be a promising prognostic biomarker for GC.Graphical

TSP50 facilitates breast cancer stem cell-like properties maintenance and epithelial-mesenchymal transition via PI3K p110α mediated activation of AKT signaling pathway

BackgroundStudies have confirmed that epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties are conducive to cancer metastasis. In recent years, testes-specific protease 50 (TSP50) has been identified as a prognostic factor and is involved in tumorigenesis regulation. However, the role and molecular mechanisms of TSP50 in EMT and CSC-like properties maintenance remain unclear.MethodsThe expression and prognostic value of TSP50 in breast cancer were excavated from public databases and explored using bioinformatics analysis. Then the expression of TSP50 and related genes was further validated by quantitative RT-PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC). In order to investigate the function of TSP50 in breast cancer, loss- and gain-of-function experiments were conducted, both in vitro and in vivo. Furthermore, immunofluorescence (IF) and immunoprecipitation (IP) assays were performed to explore the potential molecular mechanisms of TSP50. Finally, the correlation between the expression of TSP50 and related genes in breast cancer tissue microarray and clinicopathological characteristics was analyzed by IHC.ResultsTSP50 was negatively correlated with the prognosis of patients with breast cancer. TSP50 promoted CSC-like traits and EMT in both breast cancer cells and mouse xenograft tumor tissues. Additionally, inhibition of PI3K/AKT partly reversed TSP50-induced activation of CSC-like properties, EMT and tumorigenesis. Mechanistically, TSP50 and PI3K p85α regulatory subunit could competitively interact with the PI3K p110α catalytic subunit to promote p110α enzymatic activity, thereby activating the PI3K/AKT signaling pathway for CSC-like phenotypes maintenance and EMT promotion. Moreover, IHC analysis of human breast cancer specimens revealed that TSP50 expression was positively correlated with p-AKT and ALDH1 protein levels. Notably, breast cancer clinicopathological characteristics, such as patient survival time, tumor size, Ki67, pathologic stage, N stage, estrogen receptor (ER) and progesterone receptor (PR) levels, correlated well with TSP50/p-AKT/ALDH1 expression status.ConclusionThe effects of TSP50 on EMT and CSC-like properties promotion were verified to be dependent on PI3K p110α. Together, our study revealed a novel mechanism by which TSP50 facilitates the progression of breast cancer, which can provide new insights into TSP50-based breast cancer treatment strategies.

The Protective Role of miR-125b in Hepatocellular Carcinoma: Unraveling Tumor-Suppressive Mechanisms

Abstract: MicroRNAs (miRNAs) have emerged as crucial regulators of gene expression, playing pivotal roles in various biological processes, including cancer development and progression. Among them, miR-125b has garnered significant attention due to its multifaceted functional roles in human hepatocellular carcinoma (HCC). Extensive research has revealed that miR-125b plays a dual role in HCC, acting as both a tumor suppressor and an oncogene, depending on the context. As a tumor suppressor, miR-125b inhibits HCC by targeting key oncogenic pathways and genes involved in cell proliferation, migration, invasion, and angiogenesis. Its downregulation in HCC is frequently observed and correlates with aggressive tumor characteristics and poor prognosis. Conversely, miR-125b can also function as an oncogene in specific HCC subtypes or under certain conditions. It has been shown to promote HCC growth, metastasis, and therapeutic resistance by targeting tumor suppressor genes, modulating the epithelial-mesenchymal transition (EMT) process, and enhancing cancer stem cell-like properties. The upregulation of miR-125b in HCC has been associated with advanced disease stages and unfavorable clinical outcomes. Furthermore, a complex network of regulatory mechanisms influences the dysregulation of miR-125b expression in HCC. Understanding these regulatory mechanisms is crucial for deciphering the precise functional roles of miR-125b in HCC and exploring its potential as a diagnostic biomarker or therapeutic target. In the current review study, we comprehensively elucidated the diverse functional roles of miR-125b in HCC, providing a comprehensive overview of its regulatory mechanisms and impact on key cellular processes involved in HCC progression.

The HHEX-ABI2/SLC17A9 axis induces cancer stem cell-like properties and tumorigenesis in HCC

Accumulating evidence indicated that HHEX participated in the initiation and development of several cancers, but the potential roles and mechanisms of HHEX in hepatocellular carcinoma (HCC) were largely unclear. Cancer stem cells (CSCs) are responsible for cancer progression owing to their stemness characteristics. We reported that HHEX was a novel CSCs target for HCC. We found that HHEX was overexpressed in HCC tissues and high expression of HHEX was associated with poor survival. Subsequently, we found that HHEX promoted HCC cell proliferation, migration, and invasion. Moreover, bioinformatics analysis and experiments verified that HHEX promoted stem cell-like properties in HCC. Mechanistically, ABI2 serving as a co-activator of transcriptional factor HHEX upregulated SLC17A9 to promote HCC cancer stem cell-like properties and tumorigenesis. Collectively, the HHEX-mediated ABI2/SLC17A9 axis contributes to HCC growth and metastasis by maintaining the CSC population, suggesting that HHEX serves as a promising therapeutic target for HCC treatment.

LncRNA NEAT1 Promotes the Cancer Stem Cell-Like Properties of HCC by miR-128-3p/GP73 Axis

In this study, we investigated the role of long non-coding RNA NEAT1 in hepatocellular carcinoma (HCC) and its impact on liver cancer cell behavior, particularly their cancer stem cell (CSC)-like properties. We observed elevated NEAT1 levels in HCC cell lines and tissues, and this upregulation was associated with adverse clinical characteristics and poor prognosis in HCC patients. Through in vitro experiments, we found that silencing NEAT1 in HCC cells led to decreased cell proliferation, migration, invasion, and inhibited epithelial-mesenchymal transition (EMT) in Huh7 cells. Additionally, the unique surface markers of CSCs were downregulated upon NEAT1 knockdown. Further investigation revealed that NEAT1 regulates the expression of GP73 by directly binding to miR-128-3p, functioning as a competitive ceRNA to suppress miR-128-3p expression. Rescue experiments showed that inhibiting miR-128-3p expression reversed the effects of NEAT1 knockdown on HCC cell proliferation,migration, and invasion. In summary, our findings demonstrate that lncRNA NEAT1 plays a pivotal role in promoting HCC progression and enhancing CSC properties by upregulating GP7 through competitive binding to miR-128-3p. This insight into the underlying mechanism may have promising implications for the treatment of HCC.

Circ-0075305 hinders gastric cancer stem cells by indirectly disrupting TCF4–β-catenin complex and downregulation of SOX9

CircRNAs are covalently closed, single-stranded RNA that form continuous loops and play a crucial role in the initiation and progression of tumors. Cancer stem cells (CSCs) are indispensable for cancer development; however, the regulation of cancer stem cell-like properties in gastric cancer (GC) and its specific mechanism remain poorly understood. We elucidate the specific role of Circ-0075305 in GC stem cell properties. Circ-0075305 associated with chemotherapy resistance was identified by sequencing GC cells. Subsequent confirmation in both GC tissues and cell lines revealed that patients with high expression of Circ-0075305 had significantly better overall survival (OS) rates than those with low expression, particularly when treated with postoperative adjuvant chemotherapy for GC. In vitro and in vivo experiments confirmed that overexpression of Circ-0075305 can effectively reduce stem cell-like properties and enhance the sensitivity of GC cells to Oxaliplatin compared with the control group. Circ-0075305 promotes RPRD1A expression by acting as a sponge for corresponding miRNAs. The addition of LF3 (a β-catenin/TCF4 interaction antagonist) confirmed that RPRD1A inhibited the formation of the TCF4–β-catenin transcription complex through competitive to β-catenin and suppressed the transcriptional activity of stem cell markers such as SOX9 via the Wnt/β-catenin signaling pathway. This leads to the downregulation of stem cell-like property-related markers in GC. This study revealed the underlying mechanisms that regulate Circ-0075305 in GCSCs and suggests that its role in reducing β-catenin signaling may serve as a potential therapeutic candidate.

SF1: A Standardised Fraction of Clinacanthus nutans That Inhibits the Stemness Properties of Cancer Stem-Like Cells Derived from Cervical Cancer

Cancer stem cells (CSCs) are a small population of tumour cells that are responsible for tumour initiation, metastases, recurrence, and resistance to conventional therapy. Hence, targeting CSCs is crucial in the fight against cancer. SF1, a standardised fraction from Clinacanthus nutans leaf extract, has been reported to exhibit potent and selective antineoplastic effects against cervical cancer cells. In this study, the potential of SF1 to inhibit the stemness of cervical cancer stem-like cells has been evaluated. SF1 extraction was carried out using the dry column vacuum chromatography technique. SiHa cell lines were cultured as spheres in CSC-conditioned medium (cervospheres), and the IC50 of SF1 against cervospheres was determined using the OZBlue Cell Viability Kit. The effects of SF1 on the cervosphere’s stemness markers, including CD49f, CK17, SOX2, OCT4, and NANOG, were assessed using a flow cytometry assay. Self-renewal inhibition and anti-tumorigenesis effects of SF1 in cervospheres were evaluated using a sphere formation assay and a xenograft mouse model. The present study shows that SF1 treatment at an IC50 of 17.07 µg/mL inhibited the proliferation, self-renewal, and tumorigenic capacity of SiHa cervospheres in vitro and in vivo. A decrease in the expressions of CK17, SOX2, CD49f, and OCT4 in cervical CSCs indicated that SF1’s inhibitory effects were also associated with the suppression of stemness markers. These results suggest that SF1 possesses an antitumor effect against cervical CSCs and may be regarded as a promising approach to the development of targeted anticancer agents for cervical cancer.

Abstract 1566: Cancer metastasis and stemness: The metastasis-inducer MACC1 regulates LGR5 to promote cancer stem cell-like properties in colorectal cancer

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease which is thought to be initiated by colon cancer stem cells according to cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcome. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and CSC-associated invasive phenotype based on patient-derived 3D cell culture models (PD3D), patient-derived xenografts (PDX) and human CRC cell lines. We showed that CD44-enriched CSCs from PD3D models express significantly higher levels of MACC1 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PD3D and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with CSC markers CD44, NANOG and LGR5 in PD3D models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter uncovering the long-known CSC marker LGR5 as novel essential signaling mediator used by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by significant positive correlation of MACC1 and LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis-inducer MACC1 act as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs, prevent cancer recurrence and distant metastasis formation. Citation Format: Müge Erdem, Kyung Hwan Lee, Markus Hardt, Joseph Regan, Dennis Kobelt, Wolfgang Walther, Christian Regenbrecht, Ulrike S. Stein. Cancer metastasis and stemness: The metastasis-inducer MACC1 regulates LGR5 to promote cancer stem cell-like properties 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 1566.

Abstract 2789: NCAPG promotes triple-negative breast cancer stemness by a positive feedback loop with HIF-1α

Abstract Objective: Triple-negative breast cancer (TNBC) is life-threatening because of limited therapies and lack of effective therapeutic targets. NCAPG, an oncogenic marker, might be served as a new target for TNBC treatment. Here, we aimed to elucidate the role of NCAPG played in TNBC and the underlying mechanism. Design: GEO data was used to investigate the potential targets for TNBC. Patient samples and TCGA data were used to demonstrate the clinical significance. Cell migration, self-renewal ability, chemoresistance and expression of pluripotency factors were tested to detect the stemness of TNBC cells. Immunoprecipitation, ubiquitination assay and chromatin immunoprecipitation assay were utilized to investigate the mutual regulation mechanism of NCAPG and HIF-1α. Results: NCAPG was significantly overexpressed in TNBC compared with other subtypes of breast cancer and was positively correlated with poor overall survival. Elevated NCAPG expression could enhance cancer stem-like cell properties of TNBC cells. Mechanically, NCAPG positively regulated HIF-1α protein stability by interacting with HIF-1α and competitively abrogating the E3 ligase FBXW7-mediated ubiquitination and degradation towards HIF-1α. NCAPG, as a direct target gene of HIF-1α, could be in turn transcriptionally upregulated by HIF-1α. Conclusion: NCAPG promotes TNBC stemness by a HIF-1α/NCAPG positive feedback loop. NCAPG is a promising target for TNBC treatment. Citation Format: Huimin Zhang, Peiling Xie, Rui An. NCAPG promotes triple-negative breast cancer stemness by a positive feedback loop with HIF-1α [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 2789.

Morusin suppresses the stemness characteristics of gastric cancer cells induced by hypoxic microenvironment through inhibition of HIF-1α accumulation

Gastric cancer (GC) is a common, life-threatening malignancy that contributes to the global burden of cancer-related mortality, as conventional therapeutic modalities show limited effects on GC. Hence, it is critical to develop novel agents for GC therapy. Morusin, a typical prenylated flavonoid, possesses antitumor effects against various cancers. The present study aimed to demonstrate the inhibitory effect and mechanism of morusin on the stemness characteristics of human GC in vitro under hypoxia and to explore the potential molecular mechanisms. The effects of morusin on cell proliferation and cancer stem cell-like properties of the human GC cell lines SNU-1 and AGS were assessed by MTT assay, colony formation test, qRT-PCR, flow cytometry analysis, and sphere formation test under hypoxia or normoxia condition through in vitro assays. The potential molecular mechanisms underlying the effects of morusin on the stem-cell-like properties of human GC cells in vitro were investigated by qRT-PCR, western blotting assay, and immunofluorescence assay by evaluating the nuclear translocation and expression level of hypoxia-inducible factor-1α (HIF-1α). The results showed that morusin exerted growth inhibitory effects on SNU-1 and AGS cells under hypoxia in vitro. Moreover, the proportions of CD44+/CD24– cells and the sphere formation ability of SNU-1 and AGS reduced in a dose-dependent manner following morusin treatment. The expression levels of stem cell-related genes, namely Nanog, OCT4, SOX2, and HIF-1α, gradually decreased, and the nuclear translocation of the HIF-1α protein was apparently attenuated. HIF-1α overexpression partially reversed the abovementioned effects of morusin. Taken together, morusin could restrain stemness characteristics of GC cells by inhibiting HIF-1α accumulation and nuclear translocation and could serve as a promising compound for GC treatment.

The small nucleolar RNA SNORA51 enhances breast cancer stem cell-like properties via the RPL3/NPM1/c-MYC pathway.

Breast cancer stem cells (BCSCs) are key players in carcinogenesis and development. Small nucleolar RNAs (snoRNAs) seem to have a crucial influence on regulating stem cell-like properties in various cancers, but the underlying mechanism in breast cancer has not been determined. In this study, we first found that the expression of SNORA51 might be strongly and positively related to BCSCs-like properties.SNORA51 expression was assessed in breast cancer tissues (n = 158 patients) by in situ hybridization. Colony formation, cell counting kit-8,and sphere formation assays were used to detect cell proliferation and self-renewal, respectively. Wound healing and transwell assays were used to detect cell migration.Coimmunoprecipitationand molecular docking were used to determine the underlying mechanism through which SNORA51 regulates BCSCs-like properties.High SNORA51 expression was associated with a worse prognosis, overall survival,and disease-free survival,in 158 breast cancer patients and was also closely related to lymph node status, ER status, the Ki-67 index, histological grade, and TNM stage. Further analysis proved that SNORA51 could enhance and maintain stem cell-like properties, including cell proliferation, self-renewal, and migration, in breast cancer. Moreover, high SNORA51 expression could reduce nucleolar RPL3 expression, induce changes in the expression of NPM1 in the nucleolus and nucleoplasm, and ultimately increase c-MYC expression.Taken together, our findings demonstrated that SNORA51 could enhance BCSCs-like properties via the RPL3/NPM1/c-MYC pathway both in vitro and in vivo. Therefore, SNORA51 might be a significant biomarker and potential therapeutic target and might even provide a new viewpoint on the regulatory mechanism of snoRNAs in breast cancer or other malignant tumors.

USP14 promotes the cancer stem-like cell properties of OSCC via promoting SOX2 deubiquitination.

USP14 (Ubiquitin-specific-processing protease 14) is a deubiquitinating enzyme with oncogenic effects in oral squamous cell carcinoma (OSCC). This study aims to identify new substrates of USP14 and elucidate their role in modulating cancer stem-like cells (CSCs) in OSCC. Bioinformatics prediction and docking were performed using UbiBrowser 2.0 and HDOCK, respectively. OSCC cell lines and patient-derived cells were used for experimental validation, employing co-immunoprecipitation, cycloheximide chase assays, and tumor sphere formation to evaluate the effects of USP14 on SOX2 stability, ubiquitination, and CSC phenotypes. USP14 upregulation was associated with worse overall survival and progression-free interval in OSCC. USP14 interacted with SOX2 with its ubiquitin carboxyl-terminal hydrolase domain. USP14 knockdown impaired SOX2 stability by increasing its polyubiquitination. Ectopic overexpression of wild-type USP14, but not the hydrolase-deficient-mutant USP14C114A, enhanced SOX2 stability by reducing polyubiquitination. USP14 knockdown suppressed OSCC cell proliferation, colony formation, and tumor sphere formation invitro and tumor growth invivo. However, the reduction of CSC markers following USP14 knockdown was mitigated by overexpressing SOX2. These findings were verified in OSCC patient-derived CSC cells. This study revealed a USP14-SOX2 axis regulating the CSC properties of OSCC.

SALL4 promotes cancer stem-like cell phenotype and radioresistance in oral squamous cell carcinomas via methyltransferase-like 3-mediated m6A modification

Radioresistance imposes a great challenge in reducing tumor recurrence and improving the clinical prognosis of individuals having oral squamous cell carcinoma (OSCC). OSCC harbors a subpopulation of CD44(+) cells that exhibit cancer stem-like cell (CSC) characteristics are involved in malignant tumor phenotype and radioresistance. Nevertheless, the underlying molecular mechanisms in CD44( + )-OSCC remain unclear. The current investigation demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in CD44(+) cells and promotes CSCs phenotype. Using RNA-sequencing analysis, we further showed that Spalt-like transcription factor 4 (SALL4) is involved in the maintenance of CSCs properties. Furthermore, the overexpression of SALL4 in CD44( + )-OSCC cells caused radioresistance in vitro and in vivo. In contrast, silencing SALL4 sensitized OSCC cells to radiation therapy (RT). Mechanistically, we illustrated that SALL4 is a direct downstream transcriptional regulation target of METTL3, the transcription activation of SALL4 promotes the nuclear transport of β-catenin and the expression of downstream target genes after radiation therapy, there by activates the Wnt/β-catenin pathway, effectively enhancing the CSCs phenotype and causing radioresistance. Herein, this study indicates that the METTL3/SALL4 axis promotes the CSCs phenotype and resistance to radiation in OSCC via the Wnt/β-catenin signaling pathway, and provides a potential therapeutic target to eliminate radioresistant OSCC.

Effect of Pioglitazone and Cetuximab on Colon Cancer Stem-like Cell (CCSLCs) Properties.

One of the main reasons for cancer resistance to chemotherapy is the presence of cancer stem cells (CSCs) in cancer tissues. It is also believed that CSCs are the unique originators of all tumor cells. On the other hand, the Epithelial-Mesenchymal Transition pathway (EMT) can act as the main agent of metastasis. Therefore, it is possible that targeting CSCs as well as the EMT pathway could help in cancer therapy. Considering that CSCs constitute only a small percentage of the total tumor mass, enrichment before study is necessary. In our previous study, CSCs were enriched in the human colon cancer cell line HT29 by induction of EMT. These CSC-enriched HT29 cells with mesenchymal morphology were named "HT29-shE". In the present study, these cells were used to investigate the effect of pioglitazone (Pio) and Cetuximab (Cet) in order to find CSC and EMT targeting agents. The viability and IC50 rate of cells treated with different concentrations of Pio and Cet were evaluated using the MTT test. EMT and CSC markers and cell morphology were assessed in Pio and Cet treated and untreated HT29-shE cells using flow cytometry, realtime PCR, immunocytochemistry, and microscopic monitoring. The findings showed that Pio and Cet at concentrations of 250 μM and 40 μg/ml, respectively, decrease cell viability by 50%. Also, they were able to reduce the expression of CSC markers (CD133 and CD44) in the CSC enriched HT29 cell line. Furthermore, Pio and Cet could efficiently reduce the expression of vimentin as a mesenchymal marker and significantly upregulate the expression of E-cadherin as an epidermal marker of EMT and its reverse mesenchymal-- to-epithelial transition (MET). In addition, the mesenchymal morphology of HT29-shE changed into epithelial morphology after Cet treatment. Pio and Cet could inhibit EMT and reduce CSC markers in the EMT induced/CSC enriched cell line. We expect that focus on finding EMT/CSC-targeting agents like these drugs can be helpful for cancer treatment.

Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL-6/JAK-induced cancer cell plasticity.

Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6-induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.

MALAT-1 Is a Key Regulator of Epithelial-Mesenchymal Transition in Cancer: A Potential Therapeutic Target for Metastasis.

Metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) is a long intergenic non-coding RNA (lncRNA) located on chr11q13. It is overexpressed in several cancers and controls gene expression through chromatin modification, transcriptional regulation, and post-transcriptional regulation. Importantly, MALAT-1 stimulates cell proliferation, migration, and metastasis and serves a vital role in driving the epithelial-to-mesenchymal transition (EMT), subsequently acquiring cancer stem cell-like properties and developing drug resistance. MALAT-1 modulates EMT by interacting with various intracellular signaling pathways, notably the phosphoinositide 3-kinase (PI3K)/Akt and Wnt/β-catenin pathways. It also behaves like a sponge for microRNAs, preventing their interaction with target genes and promoting EMT. In addition, we have used bioinformatics online tools to highlight the disparities in the expression of MALAT-1 between normal and cancer samples using data from The Cancer Genome Atlas (TCGA). Furthermore, the intricate interplay of MALAT-1 with several essential targets of cancer progression and metastasis renders it a good candidate for therapeutic interventions. Several innovative approaches have been exploited to target MALAT-1, such as short hairpin RNAs (shRNAs), antisense oligonucleotides (ASOs), and natural products. This review emphasizes the interplay between MALAT-1 and EMT in modulating cancer metastasis, stemness, and chemoresistance in different cancers.

Biological and clinical significance of the AGE-RAGE axis in the aggressiveness and prognosis of prostate cancer.

Dietary factors and chronic hyperglycemia are linked to the formation of advanced glycation end products (AGEs) and prostate cancer (PCa) risk. The activation of the receptor for AGEs (RAGE) acts as a bridge between various RAGE ligands and certain malignancies. This study showed that the interaction of AGEs and RAGE promoted PCa cell proliferation, invasion, and autophagy-mediated survival in response to chemotherapeutic agents. RAGE-overexpressed PCa cells underwent epithelial-mesenchymal transition and showed increased cancer stem cell-like properties. In mouse xenograft models, RAGE-overexpressed cells showed more substantial tumorigenic capacity than parental cells, whereas RAGE knockdown decreased tumorigenicity. The clinical data validated a positive correlation between high AGE and RAGE expressions with poor clinical outcomes. Our findings suggest that the AGE-RAGE axis facilitates PCa progression and aggressiveness. Prostatic AGEs and RAGE expression levels are associated with PCa prognosis. Adherence to a reduced-AGE diet and targeting RAGE are potential approaches to complement and synergize with the current PCa therapies.

SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma

Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated Spink1 knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.

Up-regulation of RNA m6A methyltransferase like-3 expression contributes to arsenic and benzo[a]pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis

While arsenic or BaP alone exposure can cause lung cancer, studies showed that arsenic plus BaP co-exposure displays a significantly stronger lung tumorigenic effect. However, the underlying mechanism has not been well understood. Studies showed that RNA molecules are chemically modified. The most frequently occurring RNA modification in eukaryotic messenger RNAs is the N6-methyladenosine (m6A) methylation. This study aimed to determine whether arsenic plus BaP exposure alters RNA m6A methylation and its role in lung tumorigenic effect of arsenic plus BaP exposure. Human bronchial epithelial cells transformed by exposure to arsenic or BaP alone, and arsenic plus BaP and mouse xenograft tumorigenesis models were used in this study. It was found that arsenic plus BaP exposure-transformed cells have significantly higher levels of RNA m6A methylation than arsenic or BaP alone exposure-transformed human bronchial epithelial cells. Western blot analysis showed that arsenic plus BaP exposure greatly up-regulates the m6A writer methyltransferase like-3 (METTL3) expression levels in cultured cells and mouse lung tissues. METTL3 knockdown in cells transformed by arsenic plus BaP exposure drastically reduced their RNA m6A methylation levels. Functional studies revealed that METTL3 knockdown in cells transformed by arsenic plus BaP exposure greatly reduces their anchorage-dependent and -independent growth, cancer stem cell characters and tumorigenesis. The findings from this study suggest that arsenic plus BaP co-exposure causes epitranscriptomic dysregulation, which may contribute significantly to arsenic plus BaP co-exposure-caused synergistic lung tumorigenic effect.