Hepatitis B virus X protein and TGF-ß: partners in the carcinogenic journey of hepatocellular carcinoma.

Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-ß (TGF-ß) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-ß has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-ß interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-ß in HCC occurrence and development.

Possible Strategies to Reduce the Tumorigenic Risk of Reprogrammed Normal and Cancer Cells.

The reprogramming of somatic cells to pluripotent stem cells has immense potential for use in regenerating or redeveloping tissues for transplantation, and the future application of this method is one of the most important research topics in regenerative medicine. These cells are generated from normal cells, adult stem cells, or neoplastic cancer cells. They express embryonic stem cell markers, such as OCT4, SOX2, and NANOG, and can differentiate into all tissue types in adults, both in vitro and in vivo. However, tumorigenicity, immunogenicity, and heterogeneity of cell populations may hamper the use of this method in medical therapeutics. The risk of cancer formation is dependent on mutations of these stemness genes during the transformation of pluripotent stem cells to cancer cells and on the alteration of the microenvironments of stem cell niches at genetic and epigenetic levels. Recent reports have shown that the generation of induced pluripotent stem cells (iPSCs) derived from human fibroblasts could be induced using chemicals, which is a safe, easy, and clinical-grade manufacturing strategy for modifying the cell fate of human cells required for regeneration therapies. This strategy is one of the future routes for the clinical application of reprogramming therapy. Therefore, this review highlights the recent progress in research focused on decreasing the tumorigenic risk of iPSCs or iPSC-derived organoids and increasing the safety of iPSC cell preparation and their application for therapeutic benefits.

Human lung cancer-derived mesenchymal stem cells promote tumor growth and immunosuppression.

BACKGROUND: The presence of mesenchymal stem cells has been confirmed in some solid tumors where they serve as important components of the tumor microenvironment; however, their role in cancer has not been fully elucidated. The aim of this study was to investigate the functions of mesenchymal stem cells isolated from tumor tissues of patients with non-small cell lung cancer. RESULTS: Human lung cancer-derived mesenchymal stem cells displayed the typical morphology and immunophenotype of mesenchymal stem cells; they were nontumorigenic and capable of undergoing multipotent differentiation. These isolated cells remarkably enhanced tumor growth when incorporated into systems alongside tumor cells in vivo. Importantly, in the presence of mesenchymal stem cells, the ability of peripheral blood mononuclear cell-derived natural killer and activated T cells to mediate tumor cell destruction was significantly compromised. CONCLUSION: Collectively, these data support the notion that human lung cancer-derived mesenchymal stem cells protect tumor cells from immune-mediated destruction by inhibiting the antitumor activities of natural killer and T cells.

PKP2 induced by YAP/TEAD4 promotes malignant progression of gastric cancer.

Gastric cancer (GC) exhibits significant heterogeneity and its prognosis remains dismal. Therefore, it is essential to investigate new approaches for diagnosing and treating GC. Desmosome proteins are crucial for the advancement and growth of cancer. Plakophilin-2 (PKP2), a member of the desmosome protein family, frequently exhibits aberrant expression and is strongly associated with many tumor types' progression. In this study, we found upregulation of PKP2 in GC. Further correlation analysis showed a notable association between increased PKP2 expression and both tumor stage and poor prognosis in individuals diagnosed with gastric adenocarcinoma. In addition, our research revealed that the Yes-associated protein1 (YAP1)/TEAD4 complex could stimulate the transcriptional expression of PKP2 in GC. Elevated PKP2 levels facilitate activation of the AKT/mammalian target of rapamycin signaling pathway, thereby promoting the malignant progression of GC. By constructing a mouse model, we ultimately validated the molecular mechanism and function of PKP2 in GC. Taken together, these discoveries suggest that PKP2, as a direct gene target of YAP/TEAD4 regulation, has the potential to be used as an indication of GC progression and prognosis. PKP2 is expected to be a promising therapeutic target for GC.

Disable 2, A Versatile Tissue Matrix Multifunctional Scaffold Protein with Multifaceted Signaling: Unveiling Role in Breast Cancer for Therapeutic Revolution.

The Disabled-2 (DAB2) protein, found in 80-90% of various tumors, including breast cancer, has been identified as a potential tumor suppressor protein. On the contrary, some hypothesis suggests that DAB2 is associated with the modulation of the Ras/MAPK pathway by endocytosing the Grb/Sos1 signaling complex, which produces oncogenes and chemoresistance to anticancer drugs, leading to increased tumor growth and metastasis. DAB2 has multiple functions in several disorders and is typically under-regulated in several cancers, making it a potential target for treatment of cancer therapy. The primary function of DAB2 is the modulation of transforming growth factor- ß (TGF-ß) mediated endocytosis, which is involved in several mechanisms of cancer development, including tumor suppression through promoting apoptosis and suppressing cell proliferation. In this review, we will discuss in detail the mechanisms through which DAB2 leads to breast cancer and various advancements in employing DAB2 in the treatment of breast cancer. Additionally, we outlined its role in other diseases. We propose that upregulating DAB2 could be a novel approach to the therapeutics of breast cancer.

Disabled-2, a versatile tissue matrix multifunctional scaffold protein with multifaceted signaling: Unveiling its potential in the cancer battle.

A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/ß-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-ß) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas.

The potential role of Listeria monocytogenes in promoting colorectal adenocarcinoma tumorigenic process.

BACKGROUND: Listeria monocytogenes is a foodborne pathogen, which can cause a severe illness, especially in people with a weakened immune system or comorbidities. The interactions between host and pathogens and between pathogens and tumor cells have been debated in recent years. However, it is still unclear how bacteria can interact with tumor cells, and if this interaction can affect tumor progression and therapy. METHODS: In this study, we evaluated the involvement of L. monocytogenes in pre-neoplastic and colorectal cancer cell proliferation and tumorigenic potential. RESULTS: Our findings showed that the interaction between heat-killed L. monocytogenes and pre-neoplastic or colorectal cancer cells led to a proliferative induction; furthermore, by using a three-dimensional cell culture model, the obtained data indicated that L. monocytogenes was able to increase the tumorigenic potential of both pre-neoplastic and colorectal cancer cells. The observed effects were then confirmed as L. monocytogenes-specific, using Listeria innocua as negative control. Lastly, data suggested the Insulin Growth Factor 1 Receptor (IGF1R) cascade as one of the possible mechanisms involved in the effects induced by L. monocytogenes in the human colorectal adenocarcinoma cell line. CONCLUSIONS: These findings, although preliminary, suggest that the presence of pathogenic bacterial cells in the tumor niches may directly induce, increase, and stimulate tumor progression.

Tumor-infiltrating immune cells and survival in head and neck squamous cell carcinoma: a retrospective computational study.

The immune infiltration profiles of the tumor microenvironment have effects on the prognosis of head and neck squamous cell carcinoma (HNSCC). Whereas, HNSCC is a heterogeneous group of tumors, but past work has not taken this into consideration. Herein, we investigate the associations between survival and the function of immune cells in different tumorigenic sites of HNSCC. 1149 samples of HNSCC were collected from publicly accessible databases. Based on gene expression data, CIBERSORTx was applied to determine the proportion of 22 immune cell subpopulations. In the Cox regression model, the associations between overall survival, disease-free survival, and immune cells were examined, modeling gene expression and immune cell proportion as quartiles. Consensus cluster analysis was utilized to uncover immune infiltration profiles. Regardless of tumor sites, CD8+ T cells and activated CD4 memory T cells were associated with favorable survival, while eosinophils were the opposite. The survival of the hypopharynx, oral cavity, and larynx subsites was somewhat affected by immune cells, while the survival of the oropharynx subsite potentially was the most impacted. High expression of TIGIT, CIITA, and CXCR6 was linked to better survival, mainly in the oropharynx subsite. Immune cell clusters with four distinct survival profiles were discovered, of which the cluster with a high CD8+ T cell content had a better prognosis. The immune-infiltration pattern is related to the survival of HNSCC to varying degrees depending on the tumor sites; forthcoming studies into immune-mediated infiltration profiles will lay the groundwork for treating HNSCC with precision therapy.

Selective elimination of tumorigenic cells from mixed culture of normal and tumorigenic cells using hybrid liposomes aimed at realizing of cell therapy.

While induced pluripotent stem (iPS) cells are expected to be a cell source for regenerative medicine, they also have tumorigenic properties owing to their proliferative potential. During the manufacturing of regenerative medicine products, undifferentiated iPS cells and malignant transformed cells may be mixed in the cell culture population. Therefore, it is essential to eliminate tumorigenic cells selectively. In this study, a mixed culture of normal human fetal hepatocytes (Hc cells) and human hepatocellular carcinoma cells (HuH-7 cells) was used as a cell population model to be used as regenerative medicine products, and the selective elimination of HuH-7 cells by hybrid liposomes (HL) was analyzed. HL tended to fuse and accumulate more in HuH-7 cells due to larger fluidity of plasma membrane for HuH-7 cells than that for Hc cells. In a mixed culture of Hc and HuH-7 cells, HL selectively eliminated HuH-7 cells while allowing Hc cells to remain viable. In addition, HL treatment for the mixed culture of Hc and HuH-7 cells suppressed the tumorigenicity of HuH-7 cells. Therefore, HL selectively fused and accumulated in tumorigenic cells in a mixed cell culture of normal and tumorigenic cells, and eliminated tumorigenic cells while allowing normal cells to remain viable. The results of this study suggest the potential of HL in eliminating tumorigenic cells during the manufacturing of regenerative medicine products. Thus, HL could be expected to contribute to the development of safe regenerative medical products. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-023-00613-y.

Functional Analysis of Membrane-Associated Scaffolding Tight Junction (TJ) Proteins in Tumorigenic Characteristics of B16-F10 Mouse Melanoma Cells.

Tight junction (TJ) proteins (Tjps), Tjp1 and Tjp2, are tight junction-associated scaffold proteins that bind to the transmembrane proteins of tight junctions and the underlying cytoskeleton. In this study, we first analyzed the tumorigenic characteristics of B16-F10 melanoma cells, including cell proliferation, migration, invasion, metastatic potential, and the expression patterns of related proteins, after the CRISPR-Cas9-mediated knockout (KO) of Tjp genes. The proliferation of Tjp1 and Tjp2 KO cells significantly increased in vitro. Other tumorigenic characteristics, including migration and invasion, were significantly enhanced in Tjp1 and Tjp2 KO cells. Zonula occludens (ZO)-associated protein Claudin-1 (CLDN-1), which is a major component of tight junctions and functions in controlling cell-to-cell adhesion, was decreased in Tjp KO cells. Additionally, Tjp KO significantly stimulated tumor growth and metastasis in an in vivo mouse model. We performed a transcriptome analysis using next-generation sequencing (NGS) to elucidate the key genes involved in the mechanisms of action of Tjp1 and Tjp2. Among the various genes affected by Tjp KO-, cell cycle-, cell migration-, angiogenesis-, and cell-cell adhesion-related genes were significantly altered. In particular, we found that the Ninjurin-1 (Ninj1) and Catenin alpha-1 (Ctnna1) genes, which are known to play fundamental roles in Tjps, were significantly downregulated in Tjp KO cells. In summary, tumorigenic characteristics, including cell proliferation, migration, invasion, tumor growth, and metastatic potential, were significantly increased in Tjp1 and Tjp2 KO cells, and the knockout of Tjp genes significantly affected the expression of related proteins.

Dysregulation of delta Np63 alpha in squamous cell carcinoma and its therapeutic targeting.

The gene p63 has two isoforms -a full length transactivated isoform (TA) p63 and an amino-terminally truncated isoform, ∆Np63. DeltaNp63 alpha (∆Np63α) is the predominant splice variant of the isoform, ∆Np63 and is expressed in the basal layer of stratified epithelia. ∆Np63α that is normally essential for the epithelial lineage maintenance may be dysregulated in squamous cell carcinomas (SCCs). The pro-tumorigenic or antitumorigenic role of ∆Np63 is a highly contentious arena. ∆Np63α may act as a double-edged sword. It may either promote tumor progression, epithelial-mesenchymal transition, migration, chemoresistance, and immune-inflammatory responses, or inhibit the aforementioned phenomena depending upon cell type and tumor microenvironment. Several signaling pathways, transforming growth factor-ß, Wnt and Notch, as well as epigenetic alterations involving microRNAs, and long noncoding RNAs are regulated by ∆Np63α. This review has attempted to provide an in-depth insight into the role of ∆Np63α in the development of SCCs during different stages of tumor formation and how it may be targeted for therapeutic implications.

Establishment of an immortalized cell line derived from human adenomyosis ectopic lesions.

Because adenomyosis (AM) ectopic primary cells are hard to come by, have a short lifespan, and the characteristics that alter over time, their utility in AM research is constrained. This study aimed to establish a line of immortalized human adenomyosis ectopic cell (ihAMEC) to change this situation. Primary cells were obtained from AM ectopic lesion tissue and then infected with Simian Vacuolating Virus 40 Tag (SV40 T) lentivirus and screened to establish immortalized cells. We verified the main features and found that the ihAMEC could be cultured for more than 50 generations and the proliferation ability of ihAMEC was more active than that of primary cells. The cytoskeleton and cell types of ihAMEC were similar to primary cells and maintained a normal karyotype. The expression of epithelial-mesenchymal transition (EMT) markers, estrogen-metabolizing proteins, and estrogen/progesterone receptors in ihAMEC was similar to the expression seen in primary cells. In addition, the response of ihAMEC under estrogen treatment and Lipopolysaccharide intervention is similar to primary cells. The clonogenic ability of ihAMEC was lower than tumor cells and did not form tumors in tumorigenicity assays. Thus, ihAMEC can be used as in vitro cellular model for pathogenesis and drug development studies regarding AM.

Roles of extracellular vesicles in glioblastoma: foes, friends and informers.

Glioblastoma (GB) tumors are one of the most insidious cancers which take over the brain and defy therapy. Over time and in response to treatment the tumor and the brain cells in the tumor microenvironment (TME) undergo many genetic/epigenetic driven changes in their phenotypes and this is reflected in the cellular contents within the extracellular vesicles (EVs) they produce. With the result that some EVs try to subdue the tumor (friends of the brain), while others participate in the glioblastoma takeover (foes of the brain) in a dynamic and ever changing process. Monitoring the contents of these EVs in biofluids can inform decisions based on GB status to guide therapeutic intervention. This review covers primarily recent research describing the different cell types in the brain, as well as the tumor cells, which participate in this EV deluge. This includes EVs produced by the tumor which manipulate the transcriptome of normal cells in their environment in support of tumor growth (foes), as well as responses of normal cells which try to restrict tumor growth and invasion, including traveling to cervical lymph nodes to present tumor neo-antigens to dendritic cells (DCs). In addition EVs released by tumors into biofluids can report on the status of living tumor cells via their cargo and thus serving as biomarkers. However, EVs released by tumor cells and their influence on normal cells in the tumor microenvironment is a major factor in immune suppression and coercion of normal brain cells to join the GB "band wagon". Efforts are being made to deploy EVs as therapeutic vehicles for drugs and small inhibitory RNAs. Increasing knowledge about EVs in the TME is being utilized to track tumor progression and response to therapy and even to weaponize EVs to fight the tumor.

Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia.

Mutations or dysregulated expression of NF-kappaB activating protein (NKAP) family genes have been found in human cancers. How NKAP family gene mutations promote tumor initiation and progression remains to be determined. Here, we characterized dNKAP, the Drosophila homolog of NKAP, and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model. dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics, including tissue overgrowth, cell invasive behavior, abnormal cell polarity, and cell adhesion defects. dNKAP knockdown causes both R-loop accumulation and DNA damage, indicating the disruption of genome integrity. Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase (JNK)-dependent apoptosis and causes changes in cell proliferation in distinct cell populations. Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues. Furthermore, JNK signaling is essential for dNKAP depletion-mediated cell invasion. Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways. dNKAP knockdown and oncogenic Ras, Notch, or Yki mutations show synergies in driving tumorigenesis, further supporting the tumor-suppressive role of dNKAP. In summary, this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.

Emerging role of mesenchymal stromal cells in gynecologic cancer therapy.

Mesenchymal stromal cells (MSCs) show considerable promise in regenerative medicine with superior anti-fibrotic, immunomodulatory, and angiogenic functions. More recently, discovered with the tumor tropism, MSCs have been exploited as the basis of targeted cancer therapy. In this scenario, MSCs can directly home to tumor tissues and play anti-tumor properties. In addition, MSCs, MSC-derived exosomes and MSC-derived membranes are often developed as carriers for precisely delivering cytotoxic agents to cancer sites, including chemotherapeutic drugs, therapeutic genes, or oncolytic viruses. However, it has revealed the tumorigenic risk of MSCs as an important component within the tumor microenvironment, hampering the translation of MSC-based cancer therapies into clinical settings. Therefore, in this review, we introduce the specific tumor-tropic ability of MSCs and underlying mechanisms. We also summarize the current application of MSC-based therapeutic approaches in treating gynecologic cancers, mainly including cervical, ovarian, and endometrial cancers. Moreover, we discuss the main challenges that the current MSC-based cancer therapies are facing.

The Effect of Adipocyte-Secreted Factors in Activating Focal Adhesion Kinase-Mediated Cell Signaling Pathway towards Metastasis in Breast Cancer Cells.

Obesity-associated perturbations in the normal secretion of adipocytokines from white adipocytes can drive the metastatic progression of cancer. However, the association between obesity-induced changes in secretory factors of white adipocytes and subsequent transactivation of the downstream effector proteins impacting metastasis in breast cancer cells remains unclear. Focal adhesion kinase, a cytoplasmic signal transducer, regulates the biological phenomenon of metastasis by activating downstream targets such as beta-catenin and MMP9. Thus, the possible role of phosphorylated FAK in potentiating cancer cell migration was investigated. To elucidate this potential relationship, MCF7 (ER+), MDA-MB-231 (Triple Negative) breast cancer cells, and MCF-10A non-tumorigenic breast cells were exposed to in vitro murine adipocyte-conditioned medium derived from 3T3-L1 MBX cells differentiated to obesity with fatty acid supplementation. Our results show that the conditioned medium derived from these obese adipocytes enhanced motility and invasiveness of breast cancer cells. Importantly, no such changes were observed in the non-tumorigenic breast cells. Our results also show that increased FAK autophosphorylation was followed by increased expression of beta-catenin and MMP9 in the breast cancer cells when exposed to obese adipocyte-conditioned medium, but not in the MCF10A cells. These results indicate that adipocyte-derived secretory factors induced FAK activation through phosphorylation. This in turn increased breast cancer cell migration and invasion by activating its downstream effector proteins beta-catenin and MMP9.

Structural Characterization and Cytotoxic Activity Evaluation of Ulvan Polysaccharides Extracted from the Green Algae Ulva papenfussii.

Ulvan, a sulfated heteropolysaccharide with structural and functional properties of interest for various uses, was extracted from the green seaweed Ulva papenfussii. U. papenfussii is an unexplored Ulva species found in the South China Sea along the central coast of Vietnam. Based on dry weight, the ulvan yield was ~15% (w/w) and the ulvan had a sulfate content of 13.4 wt%. The compositional constitution encompassed L-Rhamnose (Rhap), D-Xylose (Xylp), D-Glucuronic acid (GlcAp), L-Iduronic acid (IdoAp), D-Galactose (Galp), and D-Glucose (Glcp) with a molar ratio of 1:0.19:0.35:0.52:0.05:0.11, respectively. The structure of ulvan was determined using High-Performance Liquid Chromatography (HPLC), Fourier Transform Infrared Spectroscopy (FT-IR), and Nuclear Magnetic Resonance spectroscopy (NMR) methods. The results showed that the extracted ulvan comprised a mixture of two different structural forms, namely ("A3s") with the repeating disaccharide [→4)-ß-D-GlcAp-(1→4)-α-L-Rhap 3S-(1→]n, and ("B3s") with the repeating disaccharide [→4)-α-L-IdoAp-(1→4)-α-L-Rhap 3S(1→]n. The relative abundance of A3s, and B3s was 1:1.5, respectively. The potential anticarcinogenic attributes of ulvan were evaluated against a trilogy of human cancer cell lineages. Concomitantly, Quantitative Structure-Activity Relationship (QSAR) modeling was also conducted to predict potential adverse reactions stemming from pharmacological interactions. The ulvan showed significant antitumor growth activity against hepatocellular carcinoma (IC50 ≈ 90 µg/mL), human breast cancer cells (IC50 ≈ 85 µg/mL), and cervical cancer cells (IC50 ≈ 67 µg/mL). The QSAR models demonstrated acceptable predictive power, and seven toxicity indications confirmed the safety of ulvan, warranting its candidacy for further in vivo testing and applications as a biologically active pharmaceutical source for human disease treatment.

Two-Dimensional-PAGE Coupled with nLC-MS/MS-Based Identification of Differentially Expressed Proteins and Tumorigenic Pathways in MCF7 Breast Cancer Cells Transfected for JTB Protein Silencing.

The identification of new cancer-associated genes/proteins, the characterization of their expression variation, the interactomics-based assessment of differentially expressed genes/proteins (DEGs/DEPs), and understanding the tumorigenic pathways and biological processes involved in BC genesis and progression are necessary and possible by the rapid and recent advances in bioinformatics and molecular profiling strategies. Taking into account the opinion of other authors, as well as based on our own team's in vitro studies, we suggest that the human jumping translocation breakpoint (hJTB) protein might be considered as a tumor biomarker for BC and should be studied as a target for BC therapy. In this study, we identify DEPs, carcinogenic pathways, and biological processes associated with JTB silencing, using 2D-PAGE coupled with nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) proteomics applied to a MCF7 breast cancer cell line, for complementing and completing our previous results based on SDS-PAGE, as well as in-solution proteomics of MCF7 cells transfected for JTB downregulation. The functions of significant DEPs are analyzed using GSEA and KEGG analyses. Almost all DEPs exert pro-tumorigenic effects in the JTBlow condition, sustaining the tumor suppressive function of JTB. Thus, the identified DEPs are involved in several signaling and metabolic pathways that play pro-tumorigenic roles: EMT, ERK/MAPK, PI3K/AKT, Wnt/ß-catenin, mTOR, C-MYC, NF-κB, IFN-γ and IFN-α responses, UPR, and glycolysis/gluconeogenesis. These pathways sustain cancer cell growth, adhesion, survival, proliferation, invasion, metastasis, resistance to apoptosis, tight junctions and cytoskeleton reorganization, the maintenance of stemness, metabolic reprogramming, survival in a hostile environment, and sustain a poor clinical outcome. In conclusion, JTB silencing might increase the neoplastic phenotype and behavior of the MCF7 BC cell line. The data is available via ProteomeXchange with the identifier PXD046265.

A Polyherbal Ashwagandha Formulation Exhibits Adjunctive Antitumor Efficacy Against U266 Myeloma Cells by Multi-Strategic Cytotoxic Effects: An Experimental Approach.

BACKGROUND: The present study explored the molecular mechanism of herbal (Unani) drug Habb-e-asgandh as anti-tumorigenic adjuvant therapy experimentally in U266 cells and its role in treatment of Multiple myeloma. The formulation of Habb-e-asgandh is investigated alone or as a combinatorial therapy with standard drug lenalidomide to check for its efficacy against U266 myeloma cells for prevention of drug relapse and resistance. METHODS: We performed the following assays on singly or in combination of Habb-e-asgandh-Lenalidomide treated U266 cells. The cytotoxicity evaluation done by MTT assay, we studied cell cycle kinetics by Propidium Iodide staining, mitochondrial apoptosis analysis by Annexin V/PI dual staining and JC1 staining assays. Further, anti-oxidative potential was assessed by ORAC assay and cytokine levels estimation of anti-inflammatory (TNF-alpha and IL6) and anti-angiogenic (VEGF and Ang-2) markers were done by ELISA. RESULTS: The myeloma U266 cells when treated with Habb-e-asgandh alone or in combination with standard drug lenalidomide showed cytotoxicity in dose dependent manner with promising effects at 0.4 mg/ml (IC30) and 1.5 mg/ml (IC50) inhibitory concentrations. The formulation treated cells showed modulation in cell cycle kinetics patterned by sub Go/G1 population accumulation. Furthermore, it induced mitochondrial apoptosis mainly at half maximal inhibitory concentration and in combinatorial combinations. Significantly elevated oxidative capacities (p<0.05) and reduced levels of angiogenic and pro-inflammatory markers were observed. Multiple mechanism based inhibition by Habb-e-asgandh in co-treatment with lenalidomide against myeloma cells is indicated.  Conclusion: Habb-e-asgandh formulation possess anti-tumorigenic efficacy against multiple myeloma. The adjunctive Habb-e-asgandh formulation with standard chemotherapeutic drug may prove to be a potent anti-myeloma agent in interventional therapy for Multiple myeloma if further studied in future avenues.

Cholesterol in colorectal cancer: an essential but tumorigenic precursor?

Colorectal cancer (CRC) is one of the most lethal human malignancies, and with the growth of societies and lifestyle changes, the rate of people suffering from it increases yearly. Important factors such as genetics, family history, nutrition, lifestyle, smoking, and alcohol can play a significant role in increasing susceptibility to this cancer. On the other hand, the metabolism of several macromolecules is also involved in the fate of tumors and immune cells. The evidence discloses that cholesterol and its metabolism can play a role in the pathogenesis of several cancers because there appears to be an association between cholesterol levels and CRC, and cholesterol-lowering drugs may reduce the risk. Furthermore, changes or mutations of some involved genes in cholesterol metabolism, such as CYP7A1 as well as signaling pathways, such as mitogen-activated protein kinase (MAPK), can play a role in CRC pathogenesis. This review summarized and discussed the role of cholesterol in the pathogenesis of CRC as well as available cholesterol-related therapeutic approaches in CRC.