Combinatorial Effects of 5-Fluorouracil and Menadione on Wnt/β-Catenin Pathway in Human Colorectal Cancer Cells.

The incidence and mortality rates of colorectal cancer (CRC) are alarmingly high, and the scientific community is consistently engaged in developing newer therapeutic options for cancer cure or prevention. The fluoropyrimidine drug, 5-fluorouracil (5FU), remains the first line of treatment against CRC; nevertheless, relapses frequently occur since the cells gain resistance over time through various mechanisms. Studies have highlighted the significance of combinatorial treatment of a Wnt signaling inhibitor and 5FU as a better treatment strategy to overcome 5FU resistance.

MiR-34b promotes oxidative stress and induces cellular senescence through TWIST1 in human cervical cancer.

Purpose: The aim of this research was to elucidate the role of miR-34b in cervical cancer progression and the underlying mechanism behind the miR-34b-mediated tumor suppression. The study revealed the role of miR-34b as a senescence inducer and serves as a potential therapeutic target in developing combination therapy with senotherapeutics.

Methods: MiR-34b was ectopically expressed in cervical cancer cell lines using a tetracycline inducible system and its effects on cell viability, apoptosis, senescence, DNA damage and oxidative stress were studied using MTT assay, acridine orange/ ethidium bromide staining, senescence associated β-galactosidase assay, gamma H2AX foci staining assay, western blotting and specific dyes for the detection of total and individual ROS species.

Upregulation of miR-22-3p contributes to plumbagin-mediated inhibition of Wnt signaling in human colorectal cancer cells.

The emergence of resistance and side effects for currently available drugs warrant the need for an alternative treatment regime for colorectal cancer (CRC). Several natural compounds, including plumbagin, have exhibited promising anti-cancer effects in different cancer models, although the molecular mechanisms underlying their effects remain at large. We previously reported plumbagin-mediated inhibition of Wnt signaling in CRC cells and to unravel the actual mechanism, we hypothesized the involvement of miRNAs as they have emerged as critical regulators of gene expression.

An integrated approach to understand fluid shear stress-driven and reactive oxygen species-mediated metastasis of colon adenocarcinoma through mRNA-miRNA-lncRNA-circRNA networks.

Development of colon adenocarcinoma (COAD) metastasis involves several mediators including fluid shear stress (FSS), intracellular ROS levels, and non-coding RNAs. In our present study, we identified and investigated the role of regulatory non-coding RNA molecules specifically involved in COAD metastasis and their association with FSS and ROS. Interactions between the mRNAs associated with FSS and ROS, the corresponding microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in COAD metastasis were used to generate the mRNA-miRNA-lncRNA-circRNA network.

HMGB3 inhibition by miR-142-3p/sh-RNA modulates autophagy and induces apoptosis via ROS accumulation and mitochondrial dysfunction and reduces the tumorigenic potential of human breast cancer cells.

Aims: High mobility group box (HMGB) family proteins, HMGB1, HMGB2, HMGB3, and HMGB4 are oncogenic. The oncogenic nature of HMGB1 is characterized by its association with autophagy, ROS, and MMP. Since HMGB3 is its paralog, we hypothesized that it might also modulate autophagy, ROS, and MMP.

Non-coding RNAs as emerging regulators and biomarkers in colorectal cancer.

CRC is the third most common cancer occurring worldwide and the second leading cause of cancer deaths. In the year 2020, 1,931,590 new cases of CRC and 935,173 deaths were reported. The last two decades have witnessed an intensive study of noncoding RNAs and their implications in various pathological conditions including cancer.

Design, synthesis and evaluation of 4,7-disubstituted 8-methoxyquinazoline derivatives as potential cytotoxic agents targeting β-catenin/TCF4 signaling pathway.

Overactivation of Wnt/β-catenin signaling by accumulated β-catenin in the nucleus has been shown to play a crucial role in the etiology of cancer. Interaction of β-catenin with Transcription factor 4 (TCF4) is a key step for the activation of Wnt genes in response to upstream signals of the Wnt/β-catenin pathway. Hence, down regulation of Wnt/β-catenin signaling or targeting downstream events by selective β-catenin/TCF4 protein-protein interaction inhibitors could be a potential therapeutic strategy against such cancers.

RETRA induces necroptosis in cervical cancer cells through RIPK1, RIPK3, MLKL and increased ROS production.

Cervical cancer is the fourth most prevalent cancer in women worldwide, predominantly infected with human papillomavirus (HPV). The current chemo and radiotherapies are mostly futile due to acquired resistance to apoptosis and warrant new therapeutic approaches targeting potent non-apoptotic cell death pathways to eliminate cervical cancer cells. Induction of necroptosis by pharmaceutical interventions is emerging as a promising tool in multiple apoptotic resistant cancer cells.

Metabolic modeling of host-microbe interactions for therapeutics in colorectal cancer.

The onset of colorectal cancer (CRC) is often attributed to gut bacterial dysbiosis, and thus gut microbiota are highly relevant in devising treatment strategies. Certain gut microbes, like Enterococcus spp., exhibit remarkable anti-neoplastic and probiotic properties, which can aid in silver nanoparticle (AgNPs) induced reactive oxygen species (ROS)-based CRC treatment.

miR-142-3p simultaneously targets HMGA1, HMGA2, HMGB1, and HMGB3 and inhibits tumorigenic properties and in-vivo metastatic potential of human cervical cancer cells.

Aims: High-mobility group (HMG) proteins are oncogenic in different cancers, including cervical cancer; silencing their individual expression using sh-RNAs, siRNAs, and miRNAs has had anti-tumorigenic effects, but the consequences of their collective downregulation are not known. Since multiple gene targeting is generally very effective in cancer therapy, the present study highlighted the consequences of silencing the expression of HMGA1, A2, B1, and B3 using sh-RNAs or miR-142-3p (that can potentially target HMGA1, A2, B1, and B3) in cervical cancer cell lines.

Main Methods: 3' UTR luciferase reporter assays were performed to validate HMGA1, A2, B1, and B3 as targets of miR-142-3p in human cervical cancer cells.

Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study.

Background: Survival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAF mutation is the major mutation that results in the transformation of normal cells in to an undifferentiated cancer cells via aberrant molecular signaling mechanisms. Although vemurufenib is a selective oral drug for the BRAF mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study has showed resistance to this drug in ATC.

SLC7A11/ xCT is a target of miR-5096 and its restoration partially rescues miR-5096-mediated ferroptosis and anti-tumor effects in human breast cancer cells.

Breast cancer cells evade cell death by overexpressing SLC7A11, which functions by transporting cystine into cells in exchange for intracellular glutamate facilitating glutathione synthesis and reducing reactive oxygen species (ROS)-mediated stress. Using an in silico approach, we predicted an miRNA (miR-5096) that can target and downregulate SLC7A11. We demonstrated SLC7A11 as a target of miR-5096 by 3'UTR luciferase assay and further validated it by identifying reduced mRNA and protein levels of SLC7A11 upon miR-5096 overexpression.

MicroRNA Interactome Multiomics Characterization for Cancer Research and Personalized Medicine: An Expert Review.

MicroRNAs (miRNAs) that are mutually modulated by their interacting partners (interactome) are being increasingly noted for their significant role in pathogenesis and treatment of various human cancers. Recently, miRNA interactome dissected with multiomics approaches has been the subject of focus since individual tools or methods failed to provide the necessary comprehensive clues on the complete interactome. Even though single-omics technologies such as proteomics can uncover part of the interactome, the biological and clinical understanding still remain incomplete.

Clinicopathologic implications of epithelial cell adhesion molecule expression across molecular subtypes of breast carcinoma.

Background: Epithelial cell adhesion molecule (EpCAM), a type I transmembrane protein of the epithelial tissues and known cell adhesion molecule, has been demonstrated to have critical role in carcinogenesis. In breast cancer, EpCAM expression has been associated with poor prognosis. The expression pattern of EpCAM across molecular subtypes of breast carcinoma has been studied in patients reporting to a South Indian multispecialty tertiary care hospital.

Regulation of Hippo signaling pathway in cancer: A MicroRNA perspective.

Recent studies have suggested that Hippo signaling is not only involved in controlling organ size in Drosophila but can also regulate cell proliferation, tissue homeostasis, differentiation, apoptosis and regeneration. Any dysregulation of Hippo signaling, especially the hyper activation of its downstream effectors YAP/TAZ, can lead to uncontrolled cell proliferation and malignant transformation. In majority of cancers, expression of YAP/TAZ is extremely high and this increased expression of YAP/TAZ has been shown to be an independent predictor of prognosis and indicator of increased cell proliferation, metastasis and poor survival.

Identification of mRNA and non-coding RNA hubs using network analysis in organ tropism regulated triple negative breast cancer metastasis.

Triple negative breast cancer (TNBC) is aggressive in nature, resistant to conventional therapy and often ends in organ specific metastasis. In this study, publicly available datasets were used to identify miRNA, mRNA and lncRNA hubs. Using validated mRNA-miRNA, mRNA-mRNA and lncRNA-miRNA interaction information obtained from various databases, RNA interaction networks for TNBC and its subtype specific as well as organ tropism regulated metastasis were generated.

Reactive Pt(II) center as part of redox-active quinoline-based heterocyclic scaffolds toward new anticancer leads.

New cisplatin analogs in which the diamminedichloro-Pt(II) unit is conjugated to dihydroquinoline- or tetrahydroquinoline frameworks were synthesized and subjected to biological evaluation in order to understand their effects on cellular redox homeostasis and cell viability. They exhibited better selectivity towards cancer cells (A549) compared to mice fibroblast NIH3T3 cells, with cytotoxicity in the same range as that of cisplatin. There was structure-dependent variation in the levels of ROS and were also able to induce cell death, as evidenced by accumulation of cells in sub-G1 phase.

An integrated approach for mining precise RNA-based cervical cancer staging biomarkers.

Since international federation of gynecology and obstetrics (FIGO) staging is mainly based on clinical assessment, an integrated approach for mining RNA based biomarkers for understanding the molecular deregulation of signaling pathways and RNAs in cervical cancer was proposed in this study. Publicly available data were mined for identifying significant RNAs after patient staging. Significant miRNA families were identified from mRNA-miRNA and lncRNA-miRNA interaction network analyses followed by stage specific mRNA-miRNA-lncRNA association network generation.

Vitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.

Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells.

A novel reporter system for cyclic AMP mediated gene expression in mammalian cells based on synthetic transgene expression system.

Cyclic AMP (cAMP) is an important second messenger that mediates various biological functions in both prokaryotes and eukaryotes. Due to the ever increasing significance in studying the function and modulation of cAMP-based signaling, it is important to develop a protein-based biosensor that reports the cAMP mediated gene expression. Based on a synthetic transgene approach, an artificial mammalian transactivator was developed by fusing a transcriptional regulatory element cAMP receptor protein (CRP) of Escherichia coli to the VP16 transactivation domain of Herpes simplex virus in a mammalian expression vector (pLA1) that activates CRP specific operator site present in a chimeric promoter (O- PhCMV- Luciferase) in a concentration dependent manner in mammalian cells.

Entrainment of superoxide rhythm by menadione in HCT116 colon cancer cells.

Reactive oxygen species (ROS) are primary effectors of cytotoxicity induced by many anti-cancer drugs. Rhythms in the pseudo-steady-state (PSS) levels of particular intracellular ROS in cancer cells and their relevance to drug effectiveness are unknown thus far. We report that the PSS levels of intracellular superoxide (SOX), an important ROS, exhibit an inherent rhythm in HCT116 colon cancer cells, which is entrained (reset) by the SOX inducer, menadione (MD).

Antiproliferative and Apoptotic Activities of the Medicinal Mushroom Phellinus rimosus (Agaricomycetes) on HCT116 Human Colorectal Carcinoma Cells.

Phellinus rimosus is a host-specific wood-rotting polypore that has been reported to be used by some tribes in Kerala, India, for curing mumps. We isolated a novel polysaccharide-protein complex from Ph. rimosus (PPC-Pr) that possessed significant antitumor activity.

A Feedback Loop between MicroRNA 155 (miR-155), Programmed Cell Death 4, and Activation Protein 1 Modulates the Expression of miR-155 and Tumorigenesis in Tongue Cancer.

MicroRNA 155 (miR-155) is an oncomir, generated as a noncoding RNA from the gene whose promoter activity is mainly controlled via activation protein 1 (AP-1) and NF-κB transcription factors. We found that the expression levels of miR-155 and programmed cell death 4 (Pdcd4) exhibit inverse relationships in tongue cancer cells (SAS and AWL) and tumor tissues compared to their relationships in normal FBM cells and normal tongue tissues, respectively. and studies with the 3' untranslated region (UTR) of Pdcd4 via luciferase reporter assays, quantitative PCR (qPCR), and Western blotting showed that miR-155 directly targets Pdcd4 mRNA and blocks its expression.

miR-214 activates TP53 but suppresses the expression of RELA, CTNNB1, and STAT3 in human cervical and colorectal cancer cells.

High Mobility Group AT-hook 1 (HMGA1) was identified as a target of miR-214 in human cervical and colorectal cancers (CaCx and CRC) in a previous study. While the expression of miR-214 remains suppressed, HMGA1 behaves as a potent oncogene and plays crucial roles in several aberrant signalling pathways by interacting with intermediates like RELA, CTNNB1, STAT3, and TP53 in CaCx and CRC. Hypothetically, miR-214 should be able to regulate the stabilization of some of these intermediates through the regulation of HMGA1.