MicroRNAs modulation in lung cancer: exploring dual mechanisms and clinical prospects

The global incidence of lung cancer is marked by a considerably elevated mortality rate.MicroRNAs(miRNAs)exert pivotal influence in the intricate orchestration of gene regulation,and their dysregulation can precipitate dire consequences,notably cancer.Within this context,miRNAs encapsulated in exosomes manifest a diversified impact on the landscape of lung cancer,wherein their actions may either foster angiogenesis,cell proliferation,and metastasis,or counteract these processes.This comprehensive review article discerns potential targets for the prospective development of therapeutic agents tailored for lung cancer.Tumor-suppressive miRNAs,such as miR-204,miR-192,miR-30a,miR-34a,miR-34b,miR-203,and miR-212,exhibit heightened expression and demonstrate the capacity to inhibit cellular proliferation and invasiveness.Conversely,the deleterious effects of tumor-promoting miRNAs like miR-21,miR-106a,miR-155,miR-205,and miR-210 can be attenuated through the application of their respective inhibitors.Distinct miRNAs selectively target various oncogenes,including NUAK Family Kinase 1(NUAK1),Snail Family Transcriptional Repressor 1(Snai1),Astrocyte elevated gene-1(AEG-1),Vimentin,Proliferation and apoptosis adaptor protein 15(PEA-15/PED),Hypoxia-inducible factor 1-alpha(HIF1),as well as tumor suppressor genes such as phosphatase and tensin homolog(PTEN),Suppressor of cytokine signaling 1(SOCS1),Tumor protein P53 binding protein 1(TP53BP1),and PH Domain and Leucine Rich Repeat Protein Phosphatase 2(PHLP22).This investigative approach proves invaluable in elucidating the specific miRNAs implicated in the deregulation of crucial genes pivotal to the pathogenesis of cancer.

LCRG1 SUPPRESSES TUMOR GROWTH IN VIVO BY LIPOSOME-MEDIATED GENE TRANSFER

Objective: To investigate whether LCRG1 (Laryngeal Carcinoma Related Gene 1) has tumor suppressor function. Methods: The recombinant plasmid pcDNA3.1(+)/LCRG1 was successfully constructed. The biological effects of LCRG1 on Hep-2 cell line were studied by cell transfection, cell growth observation colony formation analysis and tumorigenicity experiments. Results: The LCRG1 gene potently inhibited tumorgenesis in vitro and in vivo, as showed by dramatic growth arrest observed in cell growth analysis and suppression of anchorage-independent growth and tumorigenicity in nude mice. Conclusion: Our results suggested that LCRG1 may be a candidate of tumor suppressor gene.

Transfer of p14ARF gene in drug-resistant human breast cancer MCF-7/Adr cells inhibits proliferation and reduces doxorubicin resistance

Objective: To elucidate the effect of p14ARF gene on multidrug-resistant tumor cells. Methods: We transferred a p14ARF cDNA into p53-mutated MCF-7/Adr human breast cancer cells. Results: In this report we demonstrated for the first time that p14ARF expression was able to greatly inhibit the MCF-7/Adr cell proliferation. Furthermore, p14ARF expression resulted in decreases in MDR1 mRNA and P-glycoprotein production, which linked with the reducing resistance of MCF-7/Adr cells to doxorubicin. Conclusion: These results imply that drug resistance might be effectively reversed with the wild-type p14ARF expression in human breast cancer cells.

Matrilin-2, an extracellular adaptor protein, is needed for the regeneration of muscle, nerve and other tissues

The extracellular matrix （ECM） performs essential functions in the differentiation, maintenance and remodeling of tissues during development and regeneration, and it undergoes dynamic changes during remodeling concomitant to alterations in the cell-ECM interactions. Here we discuss recent data addressing the critical role of the widely expressed ECM protein, matrilin-2 （Matn2） in the timely onset of differentiation and regeneration processes in myogenic, neural and other tissues and in tumorigenesis. As a multiadhesion adaptor protein, it interacts with other ECM proteins and integrins. Matn2 promotes neurite outgrowth, Schwann cell migration, neuromuscular junction formation, skeletal muscle and liver regeneration and skin wound healing. Matn2 deposition by myoblasts is crucial for the timely induction of the global switch toward terminal myogenic differentiation during muscle regeneration by affecting transforming growth factor beta/bone morphogenetic protein 7/Smad and other signal transduction pathways. Depending on the type of tissue and the pathomechanism, Math2 can also promote or suppress tumor growth.

Alteration in the expression of microRNA-21 regulated target genes:Role in breast cancer

Breast cancer,also recognized as the principal cause of cancer-related deaths among women,is the second most familiar and prevalent form of cancer.New diagnostic and prognostic biomarkers that are highly specific are urgently needed for its early prognosis.MicroRNAs(miRNAs),a class of non-coding RNAs,are known to control the biological processes involving transcription,post-transcriptional and covalent modifications,splicing,translation,cell differentiation,proliferation,apoptosis,cancer progression,and invasion.Any dysregulation in miRNA expression,demonstrating their oncogenic and tumor-suppressive functions,contributes to cancer progression.MicroRNA-21(miR-21),an‘onco-miR’in breast cancer,is involved in tumor progression and metastasis by suppressing the activity of the target gene via its interaction with the 3’UTR of the target gene.The upregulation of miR-21 is observed in many instances of breast cancer.Our review aims to summarize the current understanding of miR-21 in the regulation of important cellular functions via regulation of its target genes.We discuss its biosynthesis,oncogenic function in breast cancer,and different methods used for its detection.This will increase the current understanding of the role of miR-21 in breast cancer tumorigenesis,which will offer a perception of using miR-21 as an early detection molecular prognostic and diagnostic biomarker and as a therapeutic target in breast cancer care.

Multiple subcellular localizations and functions of protein kinase Cδ in liver cancer

Protein kinase Cδ(PKCδ)is a member of the PKC family,and its implications have been reported in various biological and cancerous processes,including cell proliferation,cell death,tumor suppression,and tumor progression.In liver cancer cells,accumulating reports show the bi-functional regulation of PKCδin cell death and survival.PKCδfunction is defined by various factors,such as phosphorylation,catalytic domain cleavage,and subcellular localization.PKCδhas multiple intracellular distribution patterns,ranging from the cytosol to the nucleus.We recently found a unique extracellular localization of PKCδin liver cancer and its growth factor-like function in liver cancer cells.In this review,we first discuss the structural features of PKCδand then focus on the functional diversity of PKCδbased on its subcellular localization,such as the nucleus,cell surface,and extracellular space.These findings improve our knowledge of PKCδinvolvement in the progression of liver cancer.

The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy

The oncoprotein SET is frequently overexpressed in many types of tumors and contributes to malignant initiation and progression through multiple mechanisms,including the hijacking of the tumor suppressors p53 and PP2A.Targeting aberrant SET represents a promising strategy for cancer intervention.However,the mechanism by which endogenous SET is regulated in cancer cells remains largely unknown.Here,we identified the tumor suppressor p53 as a key regulator that transcriptionally repressed the expression of SET in both normal and cancer cells.In addition,p53 stimulated PP2A phosphatase activity via p53-mediated transcriptional repression of SET,whereby SET-mediated inhibition of PP2A was alleviated.Moreover,targeting the interaction between SET and PP2A catalytic subunit(PP2Ac)with FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55(Thr55).Therefore,our findings uncovered a previously unknown p53-SETPP2A regulatory feedback loop.To functionally potentiate this feedback loop,we designed a combined therapeutic strategy by simultaneously administrating a p53 activator and SET antagonist in cancer cells and observed a dramatic synergistic effect on tumor suppression.Our study reveals mechanistic insight into the regulation of the oncoprotein SET and raises a potential strategy for cancer therapy by stimulating the p53-SET-PP2A feedback loop.

ZMYND10 downregulates cyclins B1 and D1 to arrest cell cycle by trimethylating lysine 9 on histone 3

The BLU gene coding for zinc finger,MYND-type containing 10(ZMYND10)protein is mapped on chromosomal region 3p21.It is frequently lost in some kinds of cancers due to hypermethylation on its promoter region and identified as a tumour suppressor gene.The underlying mechanisms for BLU-mediated tumor suppression remain unclear.BLU has been reported to disturb cell cycle progression.The present study aims at examining whether ZMYND10 prevents progression of the cell cycle by targeting to repressive histone marks and downregulating the level of cyclins.Proteins structurally similar with ZMYND10 have been shown to recognize DNA sequence upstream of coding portion of the gene encoding cell cycle regulators.Enzymes,notably demethylases modifying the lysine residues are over-expressed line oncoproteins,and targeted in anti-cancer therapy.BLU was re-expressed in H1299 and HepG2 cells.The level of cyclin D1,cyclin B1 and trimethylate lysine 9 on histone 3(H3K9me3)and the binding of BLU with SIN3A(a component of the co-repressor)were detected.Cell cycle profile was measured.The evolutionary relationship between ZMYND10 and other ZMYND proteins was analysed by phylogenetic tree construction.We found that BLU expression induced G1 arrest in H1299 cells,and induced G1/G2 arrest in HepG2 cells.Cell cycle arrest was correlated with reduced activities and levels of cyclins;cyclin D1 was downregulated in H1299 cells;Both cyclin B1 and D1 were downregulated in HepG2 cells;and that BLU was associated with SIN3A.In both cell lines,the expression of H3K9me3 was induced.BLU was clustered with histone methyltransferase SMYD3 and SMYD1 on the same clade of the deduced phylogenetic tree.The results thus suggested that ZMYND10 encoded by BLU inhibited cyclins activity to prevent cell cycle progression through interaction with repressors and histone repressive marks to block the expression of genes coding for cyclins.

RELATIONSHIP BETWEEN THE MUTATION OF P53 GENE AND INFILTRATION，METASTASIS AND PROGNOSIS OF GASTRIC CARCINOMA

gastric carcinomas were examined immunohistochemically with McAb to p53 protein in order to investigate the relationship between the expression of p53 protein and histological differentiation of gastric carcinoma, and to approach the mechanism of infiltration and metastasis of gastric carcinoma. The results showed that nuclear expression of p53 protein was significantly related to tumor size, depth of invasion, lymph node and liver metastases; but not related to histological differentiation. It is suggested that the accumulation of p53 protein was increased with the progression of gastric carcinoma, and therefore the cancer clone with p53 gene mutation may play an important role in the development of tumor invasion and metastasis.

A STUDY OF MULTI-GENE EXPRESSION IN THE HIGHLY METASTASIZING HUMAN OVARIAN CANCER CELL LINE HO-8910PM AND ITS MOTHER CELL LINE HO-8910

Objective: To investigate multi gene expression in the highly metastasizing human ovarian cancer cell line HO 8910PM and its mother cell line HO 8910. Method: The expression of 9 kinds of gene products in HO 8910PM and its mother cell line HO 8910 was detected by S P immunohistochemical method. Result: Eight kinds oncogene products showed various degrees of positive expression in both HO 8910PM and HO 8910 cell lines except gene bax. The expression of P53, Cyclin D 1, CD 44 ν6 and EGFR in HO 8910PM was stronger than that in HO 8910. However, the expression of P16, nm23 in HO 8910PM was weaker than that in HO 8910. There was no significant difference on the expression of C erb B 2 and bcl 2 between the two cell lines. Conclusion: Stronger invasive and metastatic patential is found in HO 8910PM than that in HO 8910. Carcinogenesis is a result of multi oncogene and multiple step process cooperation.

P16 GENE EXPRESSION IN OVARIAN EPITHELIAL CYSTADENOCARCINOMA

P16 gene expression was measured by immnohistochemical method in poor differentiated serous cystadenocarcinoma cell line, xenograft of highly metastasizing human ovarian carcinoma in nude mice and paramn embedded tissues from 69 patients with ovarian carcinoma. The result showed that P16 gene was positive expression in HO-8910 cell of mother line,HO8910PM cell line and xenograft of highly mcatstasizing human ovarian carcinoma in nude mice. However, P16gene in the metastatic cell had a weaker expression. P16gene positive expression were also found in sl cases of 69cases (73.9%) in the ovarian epithelial carcinoma paramn embedded tissues. Comparative studies showed that the positive rate of P16 gene expression markedly reduced with the increase of pathologic grade and clinical stage,metastasis in the lymph node and decrease of 5-year survival (P<0.05, p<0.01).P16 gene is not only a controller of cytokerastic cycle, but also a key member of tumorigenic suppresser:its absence and expression degree are also correlated with the ovarian carcinoma genesis and development,especially with the metastasis of the ovarian cancer.

Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy

Mitochondria as a signaling platform play crucial roles in deciding cell fate.Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage.Mitophagy,one selective autophagy,is the key mitochondrial quality control that effectively removes damaged mitochondria.However,the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear.Here,we examined the functional implication of mitophagy in the anticancer properties of magnolol,a natural product isolated from herbal Magnolia officinalis.First,we found that magnolol induces mitochondrial depolarization,causes excessive mitochondrial fragmentation,and increases mitochondrial reactive oxygen species(mtROS).Second,magnolol induces PTEN-induced putative kinase protein 1(PINK1)-Parkin-mediated mitophagy through regulating two positive feedforward amplification loops.Third,magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway.Moreover,magnolol prolongs the survival time of tumor-bearing mice.Finally,inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy,both in vitro and in vivo.Altogether,our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis,whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol,suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy.

Tumor suppressor p53 meets microRNAs

Tumor suppressor p53 plays a central role in tumor prevention.As a transcription factor,p53 mainly exerts its function through transcription regulation of its target genes to initiate various cellular responses.To maintain its proper function,p53 is tightly regulated by a wide variety of regulators in cells.Thus,p53,its regulators and regulated genes form a complex p53 network which is composed of hundreds of genes and their products.microRNAs(miRNAs)are a class of endogenously expressed,small non-coding RNA molecules which play a key role in regulation of gene expression at the post-transcriptional level.Recent studies have demonstrated that miRNAs interact with p53 and its network at multiple levels.p53 regulates the transcription expression and the maturation of a group of miRNAs.On the other hand,miRNAs can regulate the activity and function of p53 through direct repression of p53 or its regulators in cells.These findings have demonstrated that miRNAs are important components in the p53 network,and also added another layer of complexity to the p53 network.

Tumor-responsive copper-activated disulfiram for synergetic nanocatalytic tumor therapy

Exploring alternative biomedical use of traditional drugs in different disease models is highly important as it can reduce the cost of drug development and overcome several critical issues of traditional chemodrugs such as low chemotherapeutic efficiency,severe side effect,and drug resistance.Disulfiram(DSF),a clinically approved alcohol-aversion drug,was recently demonstrated tofeature tumor-growth suppression effect along with the co-administration of Cu^(2+)species,but direct Cu^(2+)administration mode might cause severe toxicity originating from low Cu^(2+)accumulation into the tumor and nonspecific Cu^(2+)distribution-induced cytotoxicity.Based on the intriguing drug-delivery performance of nanoscale metal-organic frameworks(MOFs),we herein construct HKUST nMOFs as the Cu^(2+)self-supplying nanocarriers for efficient delivery of the D SF drug.The mildly acidic condition of tumor microenvironment initially triggered the release of Cu ions from HKUST nMOFs,which further reacted with the encapsulated DSF toform toxic Cu(DDTC)2(activation)for tumor chemotherapy.Especially,during the Cu(DDTC)2 complexation,Cu^(+)species were formed concomitantly,triggering the intratumoral nanocatalytic therapy for the generation of reactive oxygen species to synergistically destroying the tumor cells/tissue.As a result,synergetic tumor-responsive chemotherapy and nanocatalytic therapy are enabled by DSF@HKU ST nanodrugs,as demonstrated by the dominant anticancer efficacy with satisfied biocompatibility both in vitro and in vivo.The present work offers a sophisticated strategy for tumor-responsive nontoxic-to-toxic therapeutic with high biocompatibility.

Glucocorticoids suppress tumor angiogenesis and growth of prostate cancer

Hormone-refractory prostate cancer ( HRPC) sometimes is responsive to treatment with glucocorticoids, such as prednisolone, hydrocortisone and dexamethasone, but the underlying mechanisms are not well established. In a recent paper (Clin Cancer Res, 2006, 12:3003-3009), Yano et al. Hypothesized and confirmed that the therapeutic effect of glucocorticoids on HRPC is attributed to inhibition of angiogenesis. A prostate cancer cell line DU145 that expresses glucocorticoid receptor was used to study the effect of dexamethasone (Dex) on the expres-

Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylationmediated mitophagy

Parkin,an E3 ubiquitin ligase,plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy.Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level,but the underlying mechanism is poorly understood.Here,our study demonstrated that inhibition of histone deacetylase(HDAC)by treatment of HDACis activates mitophagy through mediating Parkin acetylation,leading to inhibition of cervical cancer cell proliferation.Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer,indicating the low acetylation level of Parkin.Using mass spectrometry,Parkin is identified to interact with two upstream molecules,acetylase acetyl-Co A acetyltransferase 1(ACAT1)and deacetylase HDAC2.Under treatment of suberoylanilide hydroxamic acid(SAHA),Parkin is acetylated at lysine residues 129,220 and 349,located in different domains of Parkin protein.In in vitro experiments,combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1(PINK1)and the function of Parkin in mitophagy induction and tumor suppression.In tumor xenografts,the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA.Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis,which offers a new mitophagy modulation strategy for cancer therapy.

Understanding the mechanistic regulation of ferroptosis in cancer:the gene matters

Ferroptosis has emerged as a crucial regulated cell death involved in a variety of physiological processes or pathological diseases,such as tumor suppression.Though initially being found from anticancer drug screening and considered not essential as apoptosis for growth and development,numerous studies have demonstrated that ferroptosis is tightly regulated by key genetic pathways and/or genes,including several tumor suppressors and oncogenes.In this review,we introduce the basic concepts of ferroptosis,characterized by the features of non-apoptotic,iron-dependent,and overwhelmed accumulation of lipid peroxides,and the underlying regulated circuits are considered to be pro-ferroptotic pathways.Then,we discuss several established lipid peroxidation defending systems within cells,including SLC7A11/GPX4,FSP1/CoQ,GCH1/BH4,and mitochondria DHODH/CoQ,all of which serve as anti-ferroptotic pathways to prevent ferroptosis.Moreover,we provide a comprehensive summary of the genetic regulation of ferroptosis via targeting the above-mentioned pro-ferroptotic or anti-ferroptotic pathways.The regulation of proand anti-ferroptotic pathways gives rise to more specific responses to the tumor cells in a contextdependent manner,highlighting the unceasing study and deeper understanding of mechanistic regulation of ferroptosis for the purpose of applying ferroptosis induction in cancer therapy.