Tumorigenic Cancer Research Articles

The Pathogenic Roles of lncRNAs in Glioma

Abstract: Brain cancers or intracranial cancers are among the deadliest cancers in the world. The presence of tumorigenic cancer cells in the brain and induction of poor prognosis may impact the survival/death balance. Glioma is a type of brain tumor that begins in the glial tissue. Recently, it has been reported that long non-coding RNAs (lncRNAs) with at least 200 nucleotides in length by targeting DNAs, RNAs, and proteins play essential roles in several biological processes, including growth, differentiation, and development. Recently, lncRNAs was reported to contribute to the tumorigenesis of glioma by targeting miRNAs, other ncRNAs, and mRNAs. In this review, we focused on the functional roles of lnRNAs in glioma.

Circular RNA RHBDD1 regulates tumorigenicity and ferroptosis in colorectal cancer by mediating the ELAVL1/SCD mRNA interaction.

Circular RNAs (circRNAs) are covalently closed noncoding RNA molecules that play multiple roles in tumorigenesis and metastasis. Ferroptosis is an iron-dependent, regulated form of cell death and has emerged as a promising target for cancer treatment. However, whether and how circRNAs regulate ferroptotic cell death in colorectal cancer (CRC) remains largely unknown. Three circRNA microarrays were used to screen differentially expressed circRNAs in CRC tissues. A series of functional experiments were conducted to investigate the effects of circRNA on CRC cell proliferation, migration and ferroptosis. We found that hsa_circ_0058495 (circRHBDD1), a novel circRNA, was significantly upregulated in colorectal cancer tissues and cells. The expression levels of circRHBDD1 in serum samples were strongly associated with the advancement of CRC. Silencing of circRHBDD1 remarkably suppressed the proliferation and migration of CRC cells in vitro. Moreover, the depletion of circRHBDD1 notably increased ferroptotic cell death and enhanced RSL3-induced ferroptosis in CRC cells. Mechanistically, circRHBDD1 upregulated the expression of stearoyl-CoA desaturase (SCD), a ferroptosis suppressor mediating lipid remodelling, by enhancing the ELAVL1/SCD mRNA interaction. Finally, circRHBDD1 knockdown repressed the tumorigenesis and ferroptosis of CRC cells in vivo. In conclusion, circRHBDD1 facilitates tumour progression and obstructs ferroptosis in CRC by regulating SCD expression in an ELAVL1-dependent manner.

High Serum ST2 Level Predicts Progression and Poor Prognosis of Denovomyelodysplastic Syndrome

Background: Myelodysplastic syndromes (MDS) are heterogeneous hematological stem cell malignancies with a complex pathophysiology involving immune, genetic, and epigenetic changes induced by aging, oxidative stress, and genotoxicity. Dysregulated immune responses and aberrant inflammatory signaling have been identified as critical drivers of MDS development. Recent research has highlighted the significant association of the IL-33/ST2 signaling axis with tumorigenicity and tumor immunity in various cancers. Soluble ST2 (sST2), a transmembrane-free receptor induced by IL-33, negatively regulates the IL-33/ST2 signaling pathway, and elevated levels of sST2 have been reported to correlate with poor prognosis in malignant tumors. However, the specific level of soluble ST2 and the precise role of the IL-33/ST2 signaling axis in the context of MDS remain uncertain and require further investigation. Method: This prospective study enrolled 89 newly diagnosed, untreated outpatient individuals with MDS to assess their clinical prognostic risk using the International Prognostic Scoring System-Revised (IPSS-R) and the International Prognostic Scoring System-Molecular (IPSS-M). A control group of 45 healthy donors (HD) was also included. The levels of various cytokines (sST2, IL-33, IL-2Rα, IL-6, IL-15) were measured using ELISA. Result: Our study revealed that sST2 levels in MDS patients were significantly higher compared to HD (22.18 vs. 12.43 ng/ml, p = 0.0313), with no significant difference between low and high-risk groups. The Receiver Operating Characteristic (ROC) curve analysis showed an Area Under the Curve (AUC) of 0.6140 for sST2 (p = 0.0315, 95%CI 0.5199-0.7081). Using the maximum Youden index, the optimal cut-off value for sST2 (>14.71 ng/ml) was determined with a sensitivity and specificity of 51.69% and 73.33%, respectively. Progressive events include conversion to leukemia(n=8), transfusion-dependent occurrence(n=1) and death (n=29). Patients with higher sST2 levels in both high and low-risk groups demonstrated poorer Event-Free Survival (EFS) (p = 0.0193) and Overall Survival (OS) (p = 0.0130) (Figure 1). Further, multivariate analysis identified cytokine sST2(HR = 0.337, 95%CI 0.163-0.696, P=0.003), blast percentage(HR = 0.472, 95%CI 0.237-0.940, P = 0.033), and transfusion dependence(HR = 0.367, 95%CI 0.179-0.753, P = 0.006) as independent risk factors, indicating sST2's potential in predicting prognosis and adverse event risk in MDS patients. Furthermore, sST2 exhibited a significant correlation with other inflammatory cytokines (IL-2Rα, r = 0.4152, p = 0.0005; IL-6, r = 0.4897, p = 0.0013; IL-15, r = 0.3535, p = 0.0253). This suggests that sST2 plays an active role in immune system activation and chronic inflammation. Multiple attempts to detect IL-33 expression in the serum of MDS patients were unsuccessful, indicating the need for a more sensitive and specific assay. In our study, no statistically significant difference was observed in the level of sST2 between bone marrow and peripheral blood (P=0.2197), as well as before treatment and after chemotherapy (P=0.3965). These findings indicate that sST2 is an easily detectable and relatively stable indicator. Conclusions: sST2 emerges as a significant, independent negative prognostic factor at the time of MDS diagnosis, offering valuable predictive insights into disease progression and a poor prognosis.

MTOR inhibition suppresses salinomycin-induced ferroptosis in breast cancer stem cells by ironing out mitochondrial dysfunctions

Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of the mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and thereby limits iron-mediated oxidative stress. Furthermore, integration of multi-omics data identified mitochondria as a key target of Sal action, leading to profound functional and structural alteration prevented by mTOR inhibition. On top of that, we found that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidence for the mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis pointing not only that metabolic reprogramming regulates ferroptosis, but also providing proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required in the development of an effective treatment.

Tumor Microenvironment: A Niche for Cancer Stem Cell Immunotherapy.

Tumorigenic Cancer Stem Cells (CSCs), often called tumor-initiating cells (TICs), represent a unique subset of cells within the tumor milieu. They stand apart from the bulk of tumor cells due to their exceptional self-renewal, metastatic, and differentiation capabilities. Despite significant progress in classifying CSCs, these cells remain notably resilient to conventional radiotherapy and chemotherapy, contributing to cancer recurrence. In this review, our objective is to explore novel avenues of research that delve into the distinctive characteristics of CSCs within their surrounding tumor microenvironment (TME). We will start with an overview of the defining features of CSCs and then delve into their intricate interactions with cells from the lymphoid lineage, namely T cells, B cells, and natural killer (NK) cells. Furthermore, we will discuss their dynamic interplay with myeloid lineage cells, including macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs). Moreover, we will illuminate the crosstalk between CSCs and cells of mesenchymal origin, specifically fibroblasts, adipocytes, and endothelial cells. Subsequently, we will underscore the pivotal role of CSCs within the context of the tumor-associated extracellular matrix (ECM). Finally, we will highlight pre-clinical and clinical studies that target CSCs within the intricate landscape of the TME, including CAR-T therapy, oncolytic viruses, and CSC-vaccines, with the ultimate goal of uncovering novel avenues for CSC-based cancer immunotherapy.

Colorectal Cancer Is Borrowing Blueprints from Intestinal Ontogenesis.

Colorectal tumors are heterogenous cellular systems harboring small populations of self-renewing and highly tumorigenic cancer stem cells (CSCs). Understanding the mechanisms fundamental to the emergence of CSCs and colorectal tumor initiation is crucial for developing effective therapeutic strategies. Two recent studies have highlighted the importance of developmental gene expression programs as potential therapeutic targets to suppress pro-oncogenic stem cell populations in the colonic epithelium. Specifically, a subset of aberrant stem cells was identified in preneoplastic intestinal lesions sharing significant transcriptional similarities with fetal gut development. In such aberrant stem cells, Sox9 was shown as a cornerstone for altered cell plasticity, the maintenance of premalignant stemness, and subsequent colorectal tumor initiation. Independently, chemical genomics was used to identify FDA-approved drugs capable of suppressing neoplastic self-renewal based on the ontogenetic root of a target tumor and transcriptional programs embedded in pluripotency. Here, we discuss the joint conclusions from these two approaches, underscoring the importance of developmental networks in CSCs as a novel paradigm for identifying therapeutics targeting colorectal cancer stemness.

Dual targeting of H2S synthesizing enzymes; cystathionine β-synthase and cystathionine γ-lyase by miR-939-5p effectively curbs triple negative breast cancer

IntroductionHydrogen sulfide (H2S) has been recently scrutinized for its critical role in aggravating breast cancer (BC) tumorigenicity. Several cancers aberrantly express H2S synthesizing enzymes; Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). However, their levels and interdependence in BC require further studies. ObjectivesFirstly, this study aimed to demonstrate a comparative expression profile of H2S synthesizing enzymes in BC vs normal tissue. Moreover, to investigate the reciprocal relationship between CBS and CSE and highlight the importance of dual targeting. Finally, to search for a valid dual repressor of the H2S synthesizing enzymes that could cease H2S production and reduce TNBC pathogenicity. MethodsPairwise analysis of tumor vs. normal tissues of 40 BC patients was carried out. The TNBC cell line MDA-MB-231 was transfected with oligonucleotides to study the H2S mediated molecular mechanisms. In silico screening was performed to identify dual regulator(s) for CBS and CSE. Gene expression analysis was performed using qRT-PCR and was confirmed on protein level using Western blot. TNBC hallmarks were evaluated using MTT, migration, and clonogenicity assays. H2S levels were detected using a AzMc fluorescent probe. ResultsBC tissues exhibited elevated levels of both CBS and CSE. Interestingly, upon CBS knockdown, CSE levels increased compensating for H2S production in TNBC cells, underlining the importance of dually targeting both enzymes in TNBC. In silico screening suggested miR-939-5p as a regulator of both CBS and CSE with high binding scores. Low expression levels of miR-939-5p were found in BC tissues, especially the aggressive subtypes. Ectopic expression of miR-939-5p significantly repressed CBS and CSE transcript and protein levels, diminished H2S production and attenuated TNBC hallmarks. Moreover, it improved the immune surveillance potency of TNBC cells through up regulating the NKG2D ligands, MICB and ULBP2 and reducing the immune suppressive cytokine IL-10. ConclusionThis study sheds light on the reciprocal relationship between CBS and CSE and on the importance of their dual targeting, particularly in TNBC. It also postulates miR-939-5p as a potent dual repressor for CBS and CSE overcoming their redundancy in H2S production, a mechanism that can potentially attenuate TNBC oncogenicity and improves the immunogenic response.

Study of DNA Damage-Induced MSI1 Serine-347 Phosphorylation in Regulation of Radiosensitivity in Glioblastoma Multiforme

Despite the growing therapeutic techniques, Glioblastoma Multiforme (GBM) patients have limited survival due to the location and malignancies of tumor burdens. Radiotherapy is one of the common treatments with maximal surgery and chemotherapy. However, the often radioresistance occurred in GBM results in recurrence and marginal disease control. Therefore, the medical need remains unmet to treat GBM efficiently. Musashi-1 (MSI1) is one of the RNA-binding proteins known for its high oncogenicity in many cancers, including GBM. MSI1 is highly expressed in tumors and abundant in tumorigenic cancer cells. However, the relationship between MSI1 and GBM radioresistance is still largely unknown. Three human GBM cell lines, U87-MG, 05MG, and S1R1, were used in vitro, and an orthotopic nude mouse GBM model was employed in vivo. Phos-Tag blotting and phospho-MSI1 (Ser 347) antibody helped to detect the phosphorylation level of MSI1. Ultra-low attachment dishes and 3D cell culture were performed for the tumor initiation study. Flow cytometry, immunohistochemistry staining, and confocal microscope with immunofluorescent staining provide respective biomarker expressions. We initiated our study by inducing DNA damage on GBM cell lines using ionizing radiation and an alkylating agent. With Phos-Tag and NetPhos3.1 prediction, we hypothesized that a novel phosphorylation site on MSI1 serine-347 (S347) may sense DNA damage events. To unveil the molecular mechanism, we found DNA-dependent protein kinase catalytic subunits (DNA-PKcs), one of the DNA damage repair components, physically interacted with MSI1 in the role of a kinase. We suggest that activated DNA-PKcs may phosphorylate MSI1-S347, leading to enhanced oncogenicity and subsequent malignancies. Wild-type MSI1-overexpressing GBM cells (MSI1-WT) showed better colony and sphere-forming ability, whereas loss-of-function mutation S347A deprived the oncogenic behaviors. Besides, S347A limited the cancer initiation in the orthotopic animal model compared with MSI1-WT, suggesting that phosphorylation of MSI1-S347 promotes GBM tumorigenicity both in vitro and in vivo. In addition, we noticed that CD133 (Prominin-1), a well-characterized cancer stem-like cell marker, accompanied MSI1-WT introduction but was not seen in S347A cells. Intriguingly, we identified a few members of the let-7 microRNA family, including let-7b, 7e, and 7i, who were rescued by the S347A mutation and correspondingly expressed with CD133 levels and tumorigenic abilities. This study explains a vital relationship between GBM radioresistance and a novel oncogenic post-translational modification on MSI1 S347. IR-induced DNA damage triggers DNA-PKcs activation that subsequently phosphorylates MSI1-S347, enhancing GBM tumorigenicity via let-7 pathway. Further studies on the potential regulators, either inhibiting DNA-PKcs or antagonizing agents, may provide GBM patients with an optimistic outcome.

UBE2V2 promotes metastasis by regulating EMT and predicts a poor prognosis in lung adenocarcinoma.

As a member of the ubiquitin-conjugating enzyme (E2) family, UBE2V2 demonstrates significant tumorigenicity in many cancers. However, the relationship between UBE2V2 expression and the morbidity of lung adenocarcinoma (LUAD) is still unknown. We detected the mRNA and protein expression of UBE2V2 and analyzed its relationship with clinical parameters as well as survival prognosis based on bioinformatic and immunohistochemistry (IHC) in LUAD. The signaling pathway of UBE2V2 in the development of LUAD was obtained by GSEA. The TIMER database was used to investigate the association between UBE2V2 expression and the level of infiltration of different immune cells. Finally, we explored the effects of UBE2V2 knockdown on the proliferation, apoptosis, and migration of LUAD cells. The results showed that UBE2V2 was a potential oncogene and might be considered an independent prognostic molecule for LUAD patients based on TCGA prediction (HR: 1.497 p = 0.012) and IHC (HR:1.864 p = 0.044). IHC showed that UBE2V2 was related to the following clinicopathological factors: gender (p = 0.043), stage (p = 0.042), and lymph node metastasis (p = 0.002). Finally, knockdown of UBE2V2 reduced the migration of LUAD cells by regulating EMT-related proteins. Knockdown of UBE2V2 induced LUAD cells to arrest in the G1 phase. Knockdown of UBE2V2 increased LUAD cell apoptosis and decreased proliferation, which might be related to the downregulation of PCNA and upregulation of P53 and ƳH2AX expression. Interestingly, UBE2V2 is negatively correlated with B cells, CD4+ T cells, macrophages, and dendritic cells. UBE2V2 may be a valuable therapeutic target for lung cancer.

Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis

BackgroundGastric cancer (GC) is a fatal cancer with unclear pathogenesis. In this study, we explored the function and potential mechanisms of intercellular adhesion molecule 2 (ICAM2) in the development and advancement of GC.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to quantify ICAM2 expression in harvested GC tissues and cultured cell lines. Immunohistochemical analyses were conducted on a GC tissue microarray to quantify ICAM2 expression and explore its implication on the prognosis of GC patients. In vitro experiments were carried out to reveal the biological functions of ICAM2 in GC cell lines. Further, in vivo experiments were conducted using xenograft models to assess the impact of ICAM2 on GC development and metastasis. Western blot, immunofluorescence, immunoprecipitation, luciferase assay, chromatin immunoprecipitation, and ubiquitination analysis were employed to investigate the underlying mechanisms.ResultsICAM2 expression was downregulated in GC, positively correlating with advanced T stage, distant metastasis, advanced clinical stage, vessel invasion, and shorter patient survival time. ICAM2 overexpression suppressed the proliferation, migration, invasion, metastasis of GC cells as well as their ability to form tumors, whereas ICAM2 knockdown yielded opposite results. Erythroblast transformation-specific-related gene (ERG) as a transcription factor promoted the transcription of ICAM2 by binding to the crucial response element localized within its promoter region. Further analysis revealed that ICAM2 reduced radixin (RDX) protein stability and expression. In these cells, ICAM2 bound to the RDX protein to promote the ubiquitination and degradation of RDX via NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L), and this post-translational modification resulted in the inhibition of GC.ConclusionsIn summary, this study demonstrates that ICAM2, which is induced by ERG, suppresses GC progression by enhancing the ubiquitination and degradation of RDX in a NEDD4L-dependent manner. Therefore, these results suggest that ICAM2 is a potential prognostic marker and a therapeutic target for GC.

Upregulation of SOX9 promotes the self-renewal and tumorigenicity of cervical cancer through activating the Wnt/β-catenin signaling pathway.

Sry-box9 (SOX9) maintains stem cell properties and plays crucial roles in many cancers. However, whether SOX9 is correlated with cervical cancer cell stemness and its detailed mechanism remains obscure. We studied the relationship between SOX9 and prognosis of cervical cancer through public database, and SOX9 was related to poor prognosis of cervical cancer. Elevated SOX9 expression enhanced the self-renewal properties and promotes tumorigenicity in cervical cancer. Overexpression of SOX9 could promote the expression of stem cell-related factors in cervical cancer cells and xenografts. Meanwhile, overexpression of SOX9 could also enhance the expressions of FZD10, β-catenin, and c-Myc in cervical cancer cells and xenografts, while inhibiting the expression of DDK1. The activation of Wnt pathway by chir-99 021 raised the tumor spheroid ability of SOX9 knockdown HeLa cells. In addition, SOX9 could transcriptional inhibit DKK1 and activate FZD10 and MYC by binding to their promoters to affect the Wnt/β-catenin pathway. These results demonstrated SOX9 regulated the self-renewal and tumorigenicity of cervical cancer through Wnt/β-catenin pathway by directly transcriptional activation of FZD10, MYC and transcriptional inhibition of DKK1.

A Novel Gene Signature Associated with Protein Post-translational Modification to Predict Clinical Outcomes and Therapeutic Responses of Colorectal Cancer.

Accumulated evidence highlights the biological significance of diverse protein post-translational modifications (PTMs) in tumorigenicity and progression of colorectal cancer (CRC). In this study, ten PTM patterns (ubiquitination, methylation, phosphorylation, glycosylation, acetylation, SUMOylation, citrullination, neddylation, palmitoylation, and ADP-ribosylation) were analyzed for model construction. A post-translational modification index (PTMI) with a 14-gene signature was established. CRC patients with high PTMI had a worse prognosis after validating in nine independent datasets. By incorporating PTMI with clinical features, a nomogram with excellent predictive performance was constructed. Two molecular subtypes of CRC with obvious difference in survival time were identified by unsupervised clustering. Furthermore, PTMI was related to known immunoregulators and key tumor microenvironment components. Low-PTMI patients responded better to fluorouracil-based chemotherapy and immune checkpoint blockade therapy compared to high-PTMI patients, which was validated in multiple independent datasets. However, patients with high PTMI might be sensitive to bevacizumab. In short, we established a novel PTMI model by comprehensively analyzing diverse post-translational modification patterns, which can accurately predict clinical prognosis and treatment response of CRC patients.

Non-POU Domain-Containing Octomer-Binding (NONO) protein expression and stability promotes the tumorigenicity and activation of Akt/MAPK/β-catenin pathways in human breast cancer cells

Breast cancer is one of the most common cancers with a high mortality rate, underscoring the need to identify new therapeutic targets. Here we report that non-POU domain-containing octamer-binding (NONO) protein is overexpressed in breast cancer and validated the interaction of the WW domain of PIN1 with c-terminal threonine-proline (thr-pro) motifs of NONO. The interaction of NONO with PIN1 increases the stability of NONO by inhibiting its proteasomal degradation, and this identifies PIN1 as a positive regulator of NONO in promoting breast tumor development. Functionally, silencing of NONO inhibits the growth, survival, migration, invasion, epithelial to mesenchymal transition (EMT), and stemness of breast cancer cells in vitro. A human metastatic breast cancer cell xenograft was established in transparent zebrafish (Danio rerio) embryos to study the metastatic inability of NONO-silenced breast cancer cells in vivo. Mechanistically, NONO depletion promotes the expression of the PDL1 cell-surface protein in breast cancer cells. The identification of novel interactions of NONO with c-Jun and β-catenin proteins and activation of the Akt/MAPK/β-catenin signaling suggests that NONO is a novel regulator of Akt/MAPK/β-catenin signaling pathways. Taken together, our results indicated an essential role of NONO in the tumorigenicity of breast cancer and could be a potential target for anti-cancerous drugs.C-mep14XPctyTeLC54ZqwrVideo

The Biological Role and Translational Implications of the Long Non-Coding RNA GAS5 in Breast Cancer.

The lncRNA GAS5 plays a significant role in tumorigenicity and progression of breast cancer (BC). In this review, we first summarize the role of GAS5 in cell biology, focusing on its expression data in human normal tissues. We present data on GAS5 expression in human BC tissues, highlighting its downregulation in all major BC classes. The main findings regarding the molecular mechanisms underlying GAS5 dysregulation are discussed, including DNA hypermethylation of the CpG island located in the promoter region of the gene. We focused on the action of GAS5 as a miRNA sponge, which is able to sequester microRNAs and modulate the expression levels of their mRNA targets, particularly those involved in cell invasion, apoptosis, and drug response. In the second part, we highlight the translational implications of GAS5 in BC. We discuss the current knowledge on the role of GAS5 as candidate prognostic factor, a responsive molecular therapeutic target, and a circulating biomarker in liquid biopsies with clinical importance in BC. The findings position GAS5 as a promising druggable biomolecule and stimulate the development of strategies to restore its expression levels for novel therapeutic approaches that could benefit BC patients in the future.

CD44-positive Cancer Stem-like Cells as a Potential Source of Peritoneal Metastasis After Surgery.

The role of CD44 in gastric cancer-derived peritoneal metastasis is currently unknown. It was previously shown that viable, tumorigenic cancer cells are spilled into the peritoneal cavity during surgery, providing a potential cause of peritoneal recurrence after surgery. The purpose of this study was to elucidate the mechanism of peritoneal metastasis of gastric cancer through the expression of CD44 and to propose a method for preventing peritoneal recurrence. Gastric cancer cell line MKN-45 was sorted into CD44+ and CD44- cells and then injected intraperitoneally into NOD/ShiJic-scidJcl mice. Differences in tumor-initiating capacity between the two groups were assessed using in vivo limiting dilution assays. Tumors harvested from both groups were examined for CD44 and ALDH1A1 expression using immunohistochemistry. The effects of CD44 blockade with anti-CD44 antibody on cell invasion and peritoneal metastasis formation in vivo were assessed. CD44+ cells showed significantly higher efficiency in initiating peritoneal tumor than CD44- cells. Blockade of CD44 significantly reduced peritoneal dissemination of CD44+ cells in vivo, indicating that the CD44 function of intraperitoneally disseminated cancer cells helped promote the formation of peritoneal metastasis. The margin of established tumors showed clusters of cells co-expressing CD44 and ALDH1A1. Peritoneally administered CD44- cells resulted in peritoneal metastases consisting of CD44+ and CD44- cancer cells. CD44 expressing cells are a potential source of peritoneal metastasis after surgery and could be a promising target for preventing peritoneal recurrence.

Local production of active vitamin D3 metabolites in breast cancer cells by CYP24A1 and CYP27B1

The role of vitamin D3 and its metabolites in cancer and especially as a treatment option has been widely disputed. Clinicians noting low serum 25-hydroxyvitamin D3 [25(OH)D3] levels in their patients, recommend vitamin D3 supplementation as a method of reducing the risk of cancer; however, data supporting this are inconsistent. These studies rely on systemic 25(OH)D3 as an indicator of hormone status, but 25(OH)D3 is further metabolized in the kidney and other tissues under regulation by several factors. This study examined if breast cancer cells also possess the ability to metabolize 25(OH)D3, and if so, whether the resulting metabolites are secreted locally; if this ability reflects ERα66 status; and if they possess vitamin D receptors (VDR). To address this question, estrogen receptor alpha (ERα) positive (MCF-7) and ERα negative (HCC38 and MDA-MB-231) breast cancer cell lines were examined for expression of ERα66, ERα36, CYP24A1, CYP27B1, and VDR as well as for local production of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] after treatment with 25(OH)D3. The results showed that independent of ER status, breast cancer cells express the enzymes CYP24A1 and CYP27B1, which are responsible for converting 25(OH)D3 into its dihydroxylated forms. Moreover, these metabolites are produced at levels comparable to the levels observed in blood. They are positive for VDR, indicating that they can respond to 1α,25(OH)2D3, which can upregulate CYP24A1. These findings suggest that vitamin D metabolites may contribute to the tumorigenicity of breast cancer via autocrine and/or paracrine mechanisms.

Profiling and targeting cancer stem cell signaling pathways for cancer therapeutics.

Tumorigenic cancer stem cells (CSCs) represent a subpopulation of cells within the tumor that express genetic and phenotypic profiles and signaling pathways distinct from the other tumor cells. CSCs have eluded many conventional anti-oncogenic treatments, resulting in metastases and relapses of cancers. Effectively targeting CSCs' unique self-renewal and differentiation properties would be a breakthrough in cancer therapy. A better characterization of the CSCs' unique signaling mechanisms will improve our understanding of the pathology and treatment of cancer. In this paper, we will discuss CSC origin, followed by an in-depth review of CSC-associated signaling pathways. Particular emphasis is given on CSC signaling pathways' ligand-receptor engagement, upstream and downstream mechanisms, and associated genes, and molecules. Signaling pathways associated with regulation of CSC development stand as potential targets of CSC therapy, which include Wnt, TGFβ (transforming growth factor-β)/SMAD, Notch, JAK-STAT (Janus kinase-signal transducers and activators of transcription), Hedgehog (Hh), and vascular endothelial growth factor (VEGF). Lastly, we will also discuss milestone discoveries in CSC-based therapies, including pre-clinical and clinical studies featuring novel CSC signaling pathway cancer therapeutics. This review aims at generating innovative views on CSCs toward a better understanding of cancer pathology and treatment.

Integrated network findings reveal ubiquitin-specific protease 44 overexpression suppresses tumorigenicity of liver cancer

Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related deaths worldwide. HCC is a multistep disease marked by various signaling alterations. A better understanding of the new molecular drivers of HCC could therefore provide an opportunity to develop effective diagnostic and therapeutic targets. Ubiquitin-specific protease 44 (USP44), a member of the cysteine protease family, has been reported to play a role in many cancer types. However, its contribution to HCC development remains unknown. In the present study, we observed suppression of USP44 expression in HCC tissue. Clinicopathologic analysis further showed that low USP44 expression correlated with poorer survival and a later tumor stage in HCC, suggesting that USP44 could be a predictor of poor prognosis in patients with HCC. Gain-of-function analysis in vitro demonstrated the importance of USP44 in HCC cell growth and G0/G1 cell cycle arrest. To investigate the downstream targets of USP44 and the molecular mechanisms underlying its regulation of cell proliferation in HCC, we conducted a comparative transcriptomic analysis and identified a cluster of proliferation-related genes, including CCND2, CCNG2, and SMC3. Ingenuity Pathway Analysis further delineated the gene networks controlled by USP44 through the regulation of membrane proteins and receptors, enzymes, transcriptional factors, and cyclins involved in the control of cell proliferation, metastasis, and apoptosis in HCC. To summarize, our results highlight, for the first time, the tumor-suppression role of USP44 in HCC and suggest a new prognostic biomarker in this disease.

Inorganic pyrophosphatase 1 activates the phosphatidylinositol 3-kinase/Akt signaling to promote tumorigenicity and stemness properties in colorectal cancer

Colorectal cancer (CRC) is a common malignant tumor of the human digestive tract. Inorganic pyrophosphatase 1 (PPA1) plays an imperative role in the advancement of malignant tumors, but its function in CRC is ill-defined. In this study, we inspected the functions of PPA1 in CRC. The abundance of PPA1 in CRC tissues was analyzed by utilizing publicly available data from the The Cancer Genome Atlas and Human Protein Atlas project. Cell counting kit-8 assay and 5-ethynyl-2′-deoxyuridine assay were used to evaluate the viability and proliferation of CRC cells. Bioinformatics analysis was used to forecast the PPA1 related genes and signal pathways in CRC. The protein expression was examined by western blot. The xenograft model was implemented to determine the influence of PPA1 in CRC in vivo. Proliferating cell nuclear antigen, CD133, and CD44 contents in xenograft tumors were evaluated by immunohistochemistry. In the present study, we found that the PPA1 content was heightened in CRC, and the diagnostic value of PPA1 in CRC was enormous. Overexpression of PPA1 enhanced cell proliferation and stemness properties in CRC cells, while downregulation of PPA1 had the opposite effects. PPA1 promoted the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Activation of the PI3K/Akt signaling reversed the effect of PPA1 silencing on cell proliferation and stemness properties in CRC cells. Silencing of PPA1 reduced xenograft tumor growth via modulating the PI3K/Akt signaling pathway in vivo. In conclusion, PPA1 promoted cell proliferation and stemness properties in CRC by activating the PI3K/Akt signaling pathway.

Molecularly Engineered Surfactin Analogues Induce Nonapoptotic-Like Cell Death and Increased Selectivity in Multiple Breast Cancer Cell Types.

Surfactin, a negatively charged amphiphilic lipopeptide biosurfactant, is synthesized by the bacterium Bacillus subtilis. It consists of a cyclic heptapeptide and an 11-15C β-hydroxy fatty acid. To probe how the modification of the molecular skeleton of surfactin influences its selectivity and activity against breast cancer, six synthetic surfactins were generated. Modifications were accomplished by conjugating amine-functionalized molecules to the Glu and Asp carboxyl moieties of the heptapeptide. The resulting synthetic surfactins provided a diverse series of molecules with differences in charge, size, and hydrophilicity. After purification and structural analysis, insights into biological activity and specificity were generated for each compound. Dose-dependent growth inhibition was determined for four tumorigenic breast cancer cell lines in monolayer and spheroid morphologies, as well as nontumorigenic fibroblasts and sheep erythrocytes, which were utilized to determine selectivity indices. Results indicated that two compounds, which have amplified anionic charge, had increased activity on breast cancer, with reduced activity on nontumorigenic fibroblasts and erythrocytes. Cationic derivative surf-ethylenediamine has increased activity on all cell lines tested. Novel correlations between dose-response activities and physicochemical properties of all compounds determined that there is a significant correlation between the critical micelle concentration and activity against multiple cell lines.