Molecular mechanisms of action of epigallocatechin gallate in cancer: Recent trends and advancement.

Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is an ester of epigallocatechin and gallic acid. EGCG, abundantly found in tea, is a polyphenolic flavonoid that has the potential to affect human health and disease. EGCG interacts with various recognized cellular targets and inhibits cancer cell proliferation by inducing apoptosis and cell cycle arrest. In addition, scientific evidence has illustrated the promising role of EGCG in inhibiting tumor cell metastasis and angiogenesis. It has also been found that EGCG may reverse drug resistance of cancer cells and could be a promising candidate for synergism studies. The prospective importance of EGCG in cancer treatment is owed to its natural origin, safety, and low cost which presents it as an attractive target for further development of novel cancer therapeutics. A major challenge with EGCG is its low bioavailability which is being targeted for improvement by encapsulating EGCG in nano-sized vehicles for further delivery. However, there are major limitations of the studies on EGCG, including study design, experimental bias, and inconsistent results and reproducibility among different study cohorts. Additionally, it is important to identify specific EGCG pharmacological targets in the tumor-specific signaling pathways for development of novel combined therapeutic treatments with EGCG. The present review highlights the ongoing development to identify cellular and molecular targets of EGCG in cancer. Furthermore, the role of nanotechnology-mediated EGCG combinations and delivery systems will also be discussed.

Application of curcumin nanoformulations to target folic acid receptor in cancer: Recent trends and advances.

Curcumin, derived from turmeric, has a strong anticancer potential known for millennia. The development of this phytochemical as a medicine has been hampered by several significant deficiencies, including its poor water solubility and low bioavailability. This review article discusses possibilities to overcome these bottlenecks by focusing on this natural polyphenol's nanoformulation. Moreover, preparation of curcumin conjugates containing folates as ligands for folic acid receptors can add a new important dimension in this field, allowing specific targeting of cancer cells, considering the significantly higher expression of these receptors in malignant tissues compared to normal cells. It is highly expected that simultaneous improvement of different aspects of curcumin in fighting against such a complex and multifaceted disease like cancer. Therefore, we can better comprehend cancer biology by developing a mechanistic understanding of curcumin, which will also inspire the scientific community to develop new pharmacological models, and exploration of emerging directions to revitalize application of natural products in cancer therapy.

Path of Silibinin from diet to medicine: A dietary polyphenolic flavonoid having potential anti-cancer therapeutic significance.

In the last few decades, targeting cancer by the use of dietary phytochemicals has gained enormous attention. The plausible reason and believe or mind set behind this fact is attributed to either lesser or no side effects of natural compounds as compared to the modern chemotherapeutics, or due to their conventional use as dietary components by mankind for thousands of years. Silibinin is a naturally derived polyphenol (a flavonolignans), possess following biochemical features; molecular formula C25H22O10, Molar mass: 482.44 g/mol, Boiling point 793 °C, with strikingly high antioxidant and anti-tumorigenic properties. The anti-cancer properties of Silibinin are determined by a variety of cellular pathways which include induction of apoptosis, cell cycle arrest, inhibition of angiogenesis and metastasis. In addition, Silibinin controls modulation of the expression of aberrant miRNAs, inflammatory response, and synergism with existing anti-cancer drugs. Therefore, modulation of a vast array of cellular responses and homeostatic aspects makes Silibinin an attractive chemotherapeutic agent. However, like other polyphenols, the major hurdle to declare Silibinin a translational chemotherapeutic agent, is its lesser bioavailability. After summarizing the chemistry and metabolic aspects of Silibinin, this extensive review focuses on functional aspects governed by Silibinin in chemoprevention with an ultimate goal of summarizing the evidence supporting the chemopreventive potential of Silibinin and clinical trials that are currently ongoing, at a single platform.

Impact of noncoding RNAs on cancer directed immune therapies: Now then and forever.

Accumulating evidence demonstrates that the host genome's epigenetic modifications are essential for living organisms to adapt to extreme conditions. DNA methylation, covalent modifications of histone and interassociation of noncoding RNAs facilitate the cellular manifestation of epigenetic changes in the genome. Out of various factors involved in the epigenetic programming of the host, noncoding RNAs (ncRNAs) such as microRNA (miRNA), long noncoding RNA (lncRNA), circular RNA, snoRNA and piRNA are new generation noncoding molecules that influence a variety of cellular processes like immunity, cellular differentiation and tumor development. During tumor development, temporal changes in miRNA/lncRNA rheostat influence sterile inflammatory responses accompanied by the changes in the carcinogenic signaling in the host. At the cellular level, this is manifested by the upregulation of inflammasome and inflammatory pathways, which promotes cancer-related inflammation. Given this, we discuss the potential of lncRNAs, miRNAs, circular RNA, snoRNA and piRNA in regulating inflammation and tumor development in the host.

Biosynthesis of Zinc Oxide Nanoparticles Using Catharanthus Roseus Leaves and Their Therapeutic Response in Breast Cancer (MDA-MB-231) Cells.

As the current study reports the utilization of the leaf extract of Catharanthus roseus (C.roseus) for the biological synthesis of zinc oxide nanoparticles (ZnO NPs) because of the importance of the importance of health and environment. Bioinspired synthesis were characterized using Fourier Transform Infrared Spectroscopy (FT-IR), Field Emission-Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscopy (TEM), Energy-Dispersive X-ray Spectroscopy (EDX) and X-Ray diffraction (XRD). XRD and TEM micrograph analysis revealed that the synthesized nanostructures were well-dispersed and spherical with the average particle size in the 18-30 nm range were produced. The FT-IR spectra confirmed presence of phenolic compounds that act as reducing and capping agents. Further, it suggested the possible utilization of hydroxyl groups and amides in the reduction of Zn ions and stablization of ZnO NPs. Zinc oxide nanomaterials are effective in cancer treatments, including the destruction of tumor cells with minimal damage to healthy cells. The toxicity of zinc oxide nanomaterials was checked in vitro in the human breast cancer line MDA-MB-231. Inverse relation of the percentage of viable cells to the concentration of zinc oxide nanomaterials at increasing molar levels was assessed. The cytotoxicity analysis used in the MTT test shows the substantial viable MDA-MB-231-cells despite the increased concentration of exposure to zinc oxide nanomaterials. Reduction in the ratio of viable MDA-MB-231 cells after being exposed to zinc oxide nanomaterials was compared to untreated cancerous cells. The present approach to biosynthesis is quick, inexpensive, eco-friendly, and high-rise stable nanomaterials of zinc oxide with substantial cancer potential. This is the first study that reports molar concentrations (with the lowest concentration of 10 mM) as an anticancer agent for breast cancer and potential clinical uses for synthesized zinc oxide nanomaterials. Thus, C. roseus based synthesized ZnO NPs could be explored not only as environmentally benign method but also as a potential anti-carcinogenic agent.

Role of Hedgehog and Hippo signaling pathways in cancer: A special focus on non-coding RNAs.

Despite advanced clinical and translational oncology research, mortality rates are still increasing worldwide. Recently, a class of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been well investigated in regulating biological, molecular, and cellular signaling pathways. This review article provided the current research progress on how miRNAs, lncRNAs, and circRNAs regulate Hedgehog (Hh) and Hippo signaling pathways in various cancers. These ncRNAs target both pathways' key downstream molecules and may be used for targeted cancer treatment. Moreover, Hh and Hippo signaling pathways crosstalked with each other through Gli1 of Hh pathways and YAP1/TEAD molecules of Hippo pathways during cancer progression. Additionally, Hh and Hippo signaling pathways regulate resistance against the chemo, radio, and immune therapies for several types of cancer via inducing GLI and YAP/TAZ proteins level. Therefore, to improve the treatment regime, we presented the role of various prominent phytochemicals such as curcumin, resveratrol, genistein, quercetin, paclitaxel, and silibinin in regulating lncRNAs, miRNAs, circRNA through Hedgehog and Hippo signaling pathways' constituents in cancers. We believe that knowledge obtained from this review may help make new drugs for cancer treatment in the future.

STAT signaling as a target for intervention: from cancer inflammation and angiogenesis to non-coding RNAs modulation.

As a landmark, scientific investigation in cytokine signaling and interferon-related anti-viral activity, signal transducer and activator of transcription (STAT) family of proteins was first discovered in the 1990s. Today, we know that the STAT family consists of several transcription factors which regulate various molecular and cellular processes, including proliferation, angiogenesis, and differentiation in human carcinoma. STAT family members play an active role in transducing signals from cell membrane to nucleus through intracellular signaling and thus activating gene transcription. Additionally, they are also associated with the development and progression of human cancer by facilitating inflammation, cell survival, and resistance to therapeutic responses. Accumulating evidence suggests that not all STAT proteins are associated with the progression of human malignancy; however, STAT3/5 are constitutively activated in various cancers, including multiple myeloma, lymphoma, breast cancer, prostate hepatocellular carcinoma, and non-small cell lung cancer. The present review highlights how STAT-associated events are implicated in cancer inflammation, angiogenesis and non-coding RNA (ncRNA) modulation to highlight potential intervention into carcinogenesis-related cellular processes.

Host sphingolipids: Perspective immune adjuvant for controlling SARS-CoV-2 infection for managing COVID-19 disease.

Sphingolipids are potent bioactive agents involved in the pathogenesis of various respiratory bacterial infections. To date, several sphingolipid derivatives are known, but S1P (Sphingosine-1-phosphate) and Ceramide are the best-studied sphingolipid derivatives in the context of human diseases. These are membrane-bound lipids that influence host-pathogen interactions. Based on these features, we believe that sphingolipids might control SARS-CoV-2 infection in the host. SARS-CoV-2 utilizes the ACE-II receptor (Angiotensin-converting enzyme II receptor) on epithelial cells for its entry and replication. Activation of the ACE-II receptor is indirectly associated with the activation of S1P Receptor 1 signaling which is associated with IL-6 driven fibrosis. This is expected to promote pathological responses during SARS-CoV-2 infection in COVID-19 cases. Given this, mitigating S1P signaling by application of either S1P Lyase (SPL) or S1P analog (Fingolimod / FTY720) seems to be potential approach for controlling these pathological outcomes. However, due to the immunosuppressive nature of FTY720, it can modulate hyper-inflammatory responses and only provide symptomatic relief, which may not be sufficient for controlling the novel COVID-19 infection. Since Th1 effector immune responses are essential for the clearance of infection, we believe that other sphingolipid derivatives like Cermaide-1 Phosphate with antiviral potential and adjuvant immune potential can potentially control SARS-CoV-2 infection in the host by its ability in enhancing autophagy and antigen presentation by DC to promote T cell response which can be helpful in controlling SARS-CoV-2 infection in novel COVID-19 patients.

MicroRNAs and Long Noncoding RNAs as Novel Therapeutic Targets in Estrogen Receptor-Positive Breast and Ovarian Cancers.

Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have shown to prevent metastasis and angiogenesis in estrogen receptor (ER)-positive breast and ovarian tumors. They function primarily by reducing estrogen production in ER-positive post-menopausal breast and ovarian cancer patients. Unfortunately, current AI-based therapies often have detrimental side-effects, along with acquired resistance, with increased cancer recurrence. Thus, there is an urgent need to identify novel AIs with fewer side effects and improved therapeutic efficacies. In this regard, we and others have recently suggested noncoding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), as potential molecular targets for utilization in modulating cancer hallmarks and overcoming drug resistance in several cancers, including ER-positive breast and ovarian cancer. Herein, we describe the disruptive functions of several miRNAs and lncRNAs seen in dysregulated cancer metabolism, with a focus on the gene encoding for aromatase (CYP19A1 gene) and estrogen synthesis as a novel therapeutic approach for treating ER-positive breast and ovarian cancers. Furthermore, we discuss the oncogenic and tumor-suppressive roles of several miRNAs (oncogenic miRNAs: MIR125b, MIR155, MIR221/222, MIR128, MIR2052HG, and MIR224; tumor-suppressive miRNAs: Lethal-7f, MIR27B, MIR378, and MIR98) and an oncogenic lncRNA (MIR2052HG) in aromatase-dependent cancers via transcriptional regulation of the CYP19A1 gene. Additionally, we discuss the potential effects of dysregulated miRNAs and lncRNAs on the regulation of critical oncogenic molecules, such as signal transducer, and activator of transcription 3, ß-catenin, and integrins. The overall goal of this review is to stimulate further research in this area and to facilitate the development of ncRNA-based approaches for more efficacious treatments of ER-positive breast and ovarian cancer patients, with a slight emphasis on associated treatment-delivery mechanisms.

Leishmania donovani Infection with Atypical Cutaneous Manifestations, Himachal Pradesh, India, 2014-2018.

We conducted a molecular study of parasite sequences from a cohort of cutaneous leishmaniasis patients in Himachal Pradesh, India. Results revealed atypical cutaneous disease caused by Leishmania donovani parasites. L. donovani variants causing cutaneous manifestations in this region are different from those causing visceral leishmaniasis in northeastern India.

Circulating microRNA-590-5p functions as a liquid biopsy marker in non-small cell lung cancer.

Despite the availability of various diagnostic procedures, a tissue biopsy is still indispensable for the routine diagnosis of lung cancer. However, inaccurate diagnoses can occur, leading to inefficient cancer management. In this context, use of circulating microRNAs (miRNAs) may serve as diagnostic tools as liquid biopsies, and as biomarkers to better understand the molecular mechanisms involved in the progression of cancer. We identified miR-590-5p as a potential prognostic marker in the progression of non-small cell lung cancer (NSCLC). We were able to detect this miRNA in blood plasma samples of NSCLC patients through quantitative real-time PCR. Our data showed an ~7.5-fold downregulation of miR-590-5p in NSCLC patients compared to healthy controls, which correlated with several clinicopathological features. Further, overexpression of miR-590-5p led to decreased cell viability, proliferation, colony formation, migration, and invasion potential of lung cancer cells, whereas its knockdown showed the opposite effect. In addition, the levels of several proteins involved in the epithelial-to-mesenchymal transition negatively correlated with miR-590-5p levels in lung adenocarcinoma cells and tumors of NSCLC patients. Further, dual-luciferase reporter assays identified STAT3 as a direct target of miR-590-5p, which negatively regulated STAT3 activation and its downstream signaling molecules (eg, Cyclin D1, c-Myc, Vimentin, and ß-catenin) involved in tumorigenesis. Taken together, our study suggests that miR-590-5p functions as a tumor suppressor in NSCLC through regulating the STAT3 pathway, and may serve as a useful biomarker for the diagnosis/prognosis of NSCLC, and as a potential therapeutic target for the treatment of NSCLC.

Long Non-Coding RNAs as Strategic Molecules to Augment the Radiation Therapy in Esophageal Squamous Cell Carcinoma.

Intrinsic resistance to ionizing radiation is the major impediment in the treatment and clinical management of esophageal squamous cell carcinoma (ESCC), leading to tumor relapse and poor prognosis. Although several biological and molecular mechanisms are responsible for resistance to radiotherapy in ESCC, the molecule(s) involved in predicting radiotherapy response and prognosis are still lacking, thus requiring a detailed understanding. Recent studies have demonstrated an imperative correlation amongst several long non-coding RNAs and their involvement in complex cellular networks like DNA damage and repair, cell cycle, apoptosis, proliferation, and epithelial-mesenchymal transition. Additionally, accumulating evidence has suggested abnormal expression of lncRNAs in malignant tumor cells before and after radiotherapy effects in tumor cells' sensitivity. Thus, lncRNAs indeed represent unique molecules that can influence tumor cell susceptibility for various clinical interventions. On this note, herein, we have summarized the current status of lncRNAs in augmenting resistance/sensitivity in ESCC against radiotherapy. In addition, we have also discussed various strategies to increase the radiosensitivity in ESCC cells under clinical settings.

Molecular Mechanisms of Action of Tocotrienols in Cancer: Recent Trends and Advancements.

Tocotrienols, found in several natural sources such as rice bran, annatto seeds, and palm oil have been reported to exert various beneficial health promoting properties especially against chronic diseases, including cancer. The incidence of cancer is rapidly increasing around the world not only because of continual aging and growth in global population, but also due to the adaptation of Western lifestyle behaviours, including intake of high fat diets and low physical activity. Tocotrienols can suppress the growth of different malignancies, including those of breast, lung, ovary, prostate, liver, brain, colon, myeloma, and pancreas. These findings, together with the reported safety profile of tocotrienols in healthy human volunteers, encourage further studies on the potential application of these compounds in cancer prevention and treatment. In the current article, detailed information about the potential molecular mechanisms of actions of tocotrienols in different cancer models has been presented and the possible effects of these vitamin E analogues on various important cancer hallmarks, i.e., cellular proliferation, apoptosis, angiogenesis, metastasis, and inflammation have been briefly analyzed.

Low dose radiation primed iNOS + M1macrophages modulate angiogenic programming of tumor derived endothelium.

Solid tumors are covered by stroma, which is hypoxic in nature and composed of various non-malignant components such as endothelial cells, fibroblasts, and pericytes that support tumor growth. Tumor stroma represents a mechanical barrier for tumor infiltration of CD8+ effector T cells in particular. In this context, our previous studies have demonstrated the therapeutic impact of Low-Dose Radiation (LDR)-primed and M1-retuned (iNOS+) peritumoral macrophages that produce inducible nitric oxide, have immunological roles on tumor infiltration of effector T cells, cancer-related inflammation, and subsequent tumor immune rejection in a mouse model of pancreatic cancer. These findings suggested a possible modification of tumor endothelium by LDR-primed macrophages. In line with these observations, here we demonstrate the influence of LDR in down-modulating HIF-1 in irradiated tumors in the course of polarization of irradiated tumor-associated macrophages toward an M1 phenotype. Furthermore, we demonstrate that M1 macrophages which are primed by LDR can directly influence angiogenic responses in eNOS+ endothelial cells which produce nitric oxide having both vascular and physiological roles. Furthermore, we demonstrate that naïve macrophages, upon differentiating to an M1 phenotype either by Th1 stimuli or LDR, potentially modify sphingosine-1-phosphate/VEGF-induced angiogenic signaling in tumor-derived endothelial cells with tumorigenic potential, thus indicating the significance of iNOS+ macrophages in modulating signaling in eNOS+ tumor-derived endothelium. Our study suggests that iNOS+ macrophages can activate tumor endothelium which may contribute to cancer-directed immunotherapy in particular.

Guanine holes are prominent targets for mutation in cancer and inherited disease.

Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G • C bp in the context of all 64 5'-NGNN-3' motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials). Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease.

Long non-coding RNA: A new paradigm for lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Recent advances in whole genome transcriptome analysis have enabled the identification of numerous members of a novel class of non-coding RNAs, i.e., long non-coding RNAs (lncRNAs), which play important roles in a wide range of biological processes and whose deregulation causes human disease, including cancer. Herein we provide a comprehensive survey of lncRNAs associated with lung cancer, with particular focus on the functions that either facilitate or inhibit the progression of lung cancer and the pathways involved. Emerging data on the use of lncRNAs as biomarkers for the diagnosis and prognosis of cancer are also discussed. We cast this information within the wider perspective of lncRNA biogenesis and molecular functions in the cell. Relationships that exist between lncRNAs, genome-wide transcription, and lung cancer are discussed. Deepening our understanding on these processes is critical not only from a mechanistic standpoint, but also for the development of novel biomarkers and effective therapeutic targets for cancer patients.

DHX9 helicase is involved in preventing genomic instability induced by alternatively structured DNA in human cells.

Sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures in the human genome have been implicated in stimulating genomic instability. Previously, we found that a naturally occurring intra-molecular triplex (H-DNA) caused genetic instability in mammals largely in the form of DNA double-strand breaks. Thus, it is of interest to determine the mechanism(s) involved in processing H-DNA. Recently, we demonstrated that human DHX9 helicase preferentially unwinds inter-molecular triplex DNA in vitro. Herein, we used a mutation-reporter system containing H-DNA to examine the relevance of DHX9 activity on naturally occurring H-DNA structures in human cells. We found that H-DNA significantly increased mutagenesis in small-interfering siRNA-treated, DHX9-depleted cells, affecting mostly deletions. Moreover, DHX9 associated with H-DNA in the context of supercoiled plasmids. To further investigate the role of DHX9 in the recognition/processing of H-DNA, we performed binding assays in vitro and chromatin immunoprecipitation assays in U2OS cells. DHX9 recognized H-DNA, as evidenced by its binding to the H-DNA structure and enrichment at the H-DNA region compared with a control region in human cells. These composite data implicate DHX9 in processing H-DNA structures in vivo and support its role in the overall maintenance of genomic stability at sites of alternatively structured DNA.

The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review.

Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potential advantages such as enhanced tumor inhibition, alleviated T-cell exhaustion, heightened T-cell activation, and minimized toxicity. The integration of CAR-T therapy, which targets tumor-associated antigens, with PD-1 blockade augments T-cell function and mitigates immune suppression within the tumor microenvironment. To assess the impact of combination therapy on various tumors and lymphomas, we categorized them based on six major tumor-associated antigens: mesothelin, disialoganglioside GD-2, CD-19, CD-22, CD-133, and CD-30, which are present in different tumor types. We evaluated the efficacy, complete and partial responses, and progression-free survival in both pre-clinical and clinical models. Additionally, we discussed potential implications, including the feasibility of combination immunotherapies, emphasizing the importance of ongoing research to optimize treatment strategies and improve outcomes for cancer patients. Overall, we believe combining CAR-T therapy with PD-1 blockade holds promise for the next generation of cancer immunotherapy.

Antitumor activity of genetically engineered NK-cells in non-hematological solid tumor: a comprehensive review.

Recent advancements in genetic engineering have made it possible to modify Natural Killer (NK) cells to enhance their ability to fight against various cancers, including solid tumors. This comprehensive overview discusses the current status of genetically engineered chimeric antigen receptor NK-cell therapies and their potential for treating solid tumors. We explore the inherent characteristics of NK cells and their role in immune regulation and tumor surveillance. Moreover, we examine the strategies used to genetically engineer NK cells in terms of efficacy, safety profile, and potential clinical applications. Our investigation suggests CAR-NK cells can effectively target and regress non-hematological malignancies, demonstrating enhanced antitumor efficacy. This implies excellent promise for treating tumors using genetically modified NK cells. Notably, NK cells exhibit low graft versus host disease (GvHD) potential and rarely induce significant toxicities, making them an ideal platform for CAR engineering. The adoptive transfer of allogeneic NK cells into patients further emphasizes the versatility of NK cells for various applications. We also address challenges and limitations associated with the clinical translation of genetically engineered NK-cell therapies, such as off-target effects, immune escape mechanisms, and manufacturing scalability. We provide strategies to overcome these obstacles through combination therapies and delivery optimization. Overall, we believe this review contributes to advancing NK-cell-based immunotherapy as a promising approach for cancer treatment by elucidating the underlying mechanisms, evaluating preclinical and clinical evidence, and addressing remaining challenges.

LINC00324 promotes cell proliferation and metastasis of esophageal squamous cell carcinoma through sponging miR-493-5p via MAPK signaling pathway.

Long non-coding RNAs have been demonstrated to promote proliferation and metastasis via regulating the miRNA/mRNA regulatory axis in various malignancies. Based on our preliminary study, we investigated the mechanism of LINC00324 through miR-493-5p/MAPK1 in esophageal squamous cell carcinoma (ESCC) pathogenesis. Herein, we confirmed that LINC00324 is significantly upregulated in ESCC primary cells and esophageal squamous cell carcinoma cell line KYSE-70. Silencing of LINC00324 modulates cell proliferation markers, p21, p27, c-Myc, and Cyclin D1 and epithelial-to-mesenchymal transition markers, slug, snail, ZEB1, vimentin, ZO-1, and E-cadherin protein expression in ESCC. Through bioinformatics and dual luciferase reporter assays, we identified miR-493-5p as the direct target molecule of LINC00324. We further revealed that LINC00324 negatively regulates miR-493-5p expression in ESCC. Moreover, our multiple gain-and loss-of-functional experiments proved that a combination of miR-493-5p and LINC00324 significantly rescued ESCC cell proliferation and metastatic phenotypes. Mechanistically, LINC00324 promotes ESCC pathogenesis by acting as a competing endogenous RNA and sponges miR-493-5p activity thereby activating MAPK1 during ESCC progression. We believe that targeting LINC00324 /miR-493-5p/MAPK1 axis may provide new therapeutic avenues for ESCC.