Altered gut microbiome drives heightened pain sensitivity in a murine model of metastatic triple-negative breast cancer.

The microbiota residing in the gut environment is essential for host homeostasis. Increasing evidence suggests that microbial perturbation (dysbiosis) regulates cancer initiation and progression at local and distant sites. Here, we have identified microbial dysbiosis with the depletion of commensal bacteria as a host-intrinsic factor associated with metastatic dissemination to the bone. Using a mouse model of triple-negative mammary cancer, we demonstrate that a pre-established disruption of microbial homeostasis using an antibiotic cocktail increases tumor growth, enhanced circulating tumor cells, and subsequent dissemination to the bone. We found that the presence of pathogenic bacteria and loss of commensal bacteria in an antibiotic-induced gut environment is associated with sustained inflammation. Increased secretion of G-CSF and MMP-9 in intestinal tissues, followed by increased neutrophil infiltration and severe systemic inflammation in tumor-bearing mice, indicates the direct consequence of a dysbiotic microbiome. Increased neutrophil infiltration to the bone metastatic niche facilitates extravasation and transendothelial migration of tumor cells. It provides a novel, pre-established, and favorable environment to form an immunosuppressive pre-metastatic niche. The presence of tumor cells in immunosuppressive metastatic tumor niche disrupts the balance between osteoblasts and osteoclasts, promotes osteoclast differentiation, and remodels the bone structure. Excessive bone resorption by osteoclasts causes bone degradation and ultimately causes extreme pain in a bone metastatic mouse model. In clinical settings, bone metastasis is associated with intractable severe pain that severely compromises the quality of life in these patients.

Estrone, the major postmenopausal estrogen, binds ERa to induce SNAI2, epithelial-to-mesenchymal transition, and ER+ breast cancer metastasis.

Recent work showed that the dominant post-menopausal estrogen, estrone, cooperates with nuclear factor κB (NF-κB) to stimulate inflammation, while pre-menopausal 17ß-estradiol opposes NF-κB. Here, we show that post-menopausal estrone, but not 17ß-estradiol, activates epithelial-to-mesenchymal transition (EMT) genes to stimulate breast cancer metastasis. HSD17B14, which converts 17ß-estradiol to estrone, is higher in cancer than normal breast tissue and in metastatic than primary cancers and associates with earlier metastasis. Treatment with estrone, but not 17ß-estradiol, and HSD17B14 overexpression both stimulate an EMT, matrigel invasion, and lung, bone, and liver metastasis in estrogen-receptor-positive (ER+) breast cancer models, while HSD17B14 knockdown reverses the EMT. Estrone:ERα recruits CBP/p300 to the SNAI2 promoter to induce SNAI2 and stimulate an EMT, while 17ß-estradiol:ERα recruits co-repressors HDAC1 and NCOR1 to this site. Present work reveals novel differences in gene regulation by these estrogens and the importance of estrone to ER+ breast cancer progression. Upon loss of 17ß-estradiol at menopause, estrone-liganded ERα would promote ER+ breast cancer invasion and metastasis.

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer.

Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.

Leptin secreted from testicular microenvironment modulates hedgehog signaling to augment the endogenous function of Leydig cells.

Although testosterone deficiency (TD) may be present in one out of five men 40 years or older, the factors responsible for TD remain largely unknown. Leydig stem cells (LSCs) differentiate into adult Leydig cells (ALC) and produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. However, recent studies have suggested that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells (PMC), plays an instrumental role in LSC differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). It was hypothesized that the TME releases paracrine factors to modulate LSC differentiation. For this purpose, cells (Sertoli, PMCs, LSCs, and ALCs) were extracted from men undergoing testis biopsies for sperm retrieval and were evaluated for the paracrine factors in the presence or absence of the TME (Sertoli and PMC). The results demonstrated that TME secretes leptin, which induces LSC differentiation and increases testosterone production. Leptin's effects on LSC differentiation and testosterone production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, leptin binds to the leptin receptor on LSCs and induces DHH signaling to modulate LSC differentiation. Leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effect on leptin levels. Taken together, these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD.

Current Treatment Modalities Targeting Tumor Microenvironment in Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) is responsible for significant cancer-related morbidity and mortality following local treatment failure in men. The initial stages of PCa are typically managed with a combination of surgical resection and/or androgen deprivation therapy (ADT). Unfortunately, a significant proportion of PCa continues to progress despite being at castrate levels of testosterone (<50 ng/dl), at which point it is coined castration-resistant prostate cancer (CRPC). In recent years, many novel therapeutics and drug combinations have been created for CRPC patients. These include immune checkpoint inhibitors, chemokine receptor antagonists, steroidogenic enzyme inhibition, and novel tyrosine kinase inhibitors as well as combinations of drugs. The selection of the most appropriate therapy depends on several factors like stage of the disease, age of the patient, metastasis, functional status, and response towards previous therapies. Here, we review the current state of the literature regarding treatment modalities, focusing on the treatment recommendations per the American Urological Association (AUA), recent clinical trials, and their limitations. An accurate and reliable overview of the strengths and limitations of PCa therapeutics could also allow personalized therapeutic interventions against PCa.

Vitamin C sensitizes triple negative breast cancer to PI3K inhibition therapy.

Rationale: The clinical use of PI3K inhibitors, such as buparlisib, has been plagued with toxicity at effective doses. The aim of this study is to determine if vitamin C, a potent epigenetic regulator, can improve the therapeutic outcome and reduce the dose of buparlisib in treating PIK3CA-mutated triple negative breast cancer (TNBC). Methods: The response of TNBC cells to buparlisib was assessed by EC50 measurements, apoptosis assay, clonogenic assay, and xenograft assay in mice. Molecular approaches including Western blot, immunofluorescence, RNA sequencing, and gene silencing were utilized as experimental tools. Results: Treatment with buparlisib at lower doses, along with vitamin C, induced apoptosis and inhibited the growth of TNBC cells in vitro. Vitamin C via oral delivery rendered a sub-therapeutic dose of buparlisib able to inhibit TNBC xenograft growth and to markedly block metastasis in mice. We discovered that buparlisib and vitamin C coordinately reduced histone H3K4 methylation by enhancing the nuclear translocation of demethylase, KDM5, and by serving as a cofactor to promote KDM5-mediated H3K4 demethylation. The expression of genes in the PI3K pathway, such as AKT2 and mTOR, was suppressed by vitamin C in a KDM5-dependent manner. Vitamin C and buparlisib cooperatively blocked AKT phosphorylation. Inhibition of KDM5 largely abolished the effect of vitamin C on the response of TNBC cells to buparlisib. Additionally, vitamin C and buparlisib co-treatment changed the expression of genes, including PCNA and FILIP1L, which are critical to cancer growth and metastasis. Conclusion: Vitamin C can be used to reduce the dosage of buparlisib needed to produce a therapeutic effect, which could potentially ease the dose-dependent side effects in patients.

The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development.

Many inflammation-associated diseases, including cancers, increase in women after menopause and with obesity. In contrast to anti-inflammatory actions of 17ß-estradiol, we find estrone, which dominates after menopause, is pro-inflammatory. In human mammary adipocytes, cytokine expression increases with obesity, menopause, and cancer. Adipocyte:cancer cell interaction stimulates estrone- and NFκB-dependent pro-inflammatory cytokine upregulation. Estrone- and 17ß-estradiol-driven transcriptomes differ. Estrone:ERα stimulates NFκB-mediated cytokine gene induction; 17ß-estradiol opposes this. In obese mice, estrone increases and 17ß-estradiol relieves inflammation. Estrone drives more rapid ER+ breast cancer growth in vivo. HSD17B14, which converts 17ß-estradiol to estrone, associates with poor ER+ breast cancer outcome. Estrone and HSD17B14 upregulate inflammation, ALDH1 activity, and tumorspheres, while 17ß-estradiol and HSD17B14 knockdown oppose these. Finally, a high intratumor estrone:17ß-estradiol ratio increases tumor-initiating stem cells and ER+ cancer growth in vivo. These findings help explain why postmenopausal ER+ breast cancer increases with obesity, and offer new strategies for prevention and therapy.

Vitamin C supplementation expands the therapeutic window of BETi for triple negative breast cancer.

BACKGROUND: Bromodomain and extra-terminal inhibitors (BETi) have shown efficacy for the treatment of aggressive triple negative breast cancer (TNBC). However, BETi are plagued by a narrow therapeutic window as manifested by severe toxicities at effective doses. Therefore, it is a limitation to their clinical implementation in patient care. METHODS: The impact of vitamin C on the efficacy of small compounds including BETi was assessed by high-throughput screening. Co-treatment of TNBC by BETi especially JQ1 and vitamin C was evaluated in vitro and in vivo. FINDINGS: High-throughput screening revealed that vitamin C improves the efficacy of a number of structurally-unrelated BETi including JQ1, I-BET762, I-BET151, and CPI-203 in treating TNBC cells. The synergy between BETi and vitamin C is due to suppressed histone acetylation (H3ac and H4ac), which is in turn caused by upregulated histone deacetylase 1 (HDAC1) expression upon vitamin C addition. Treatment with JQ1 at lower doses together with vitamin C induces apoptosis and inhibits the clonogenic ability of cultured TNBC cells. Oral vitamin C supplementation renders a sub-therapeutic dose of JQ1 able to inhibit human TNBC xenograft growth and metastasis in mice. INTERPRETATION: Vitamin C expands the therapeutic window of BETi by sensitizing TNBC to BETi. Using vitamin C as a co-treatment, lower doses of BETi could be used to achieve an increased therapeutic index in patients, which will translate to a reduced side effect profile. FUND: University of Miami Sylvester Comprehensive Cancer Center, Bankhead Coley Cancer Research program (7BC10), Flight Attendant Medical Research Institute, and NIH R21CA191668 (to GW) and 1R56AG061911 (to CW and CHV).

A Prokineticin-Driven Epigenetic Switch Regulates Human Epicardial Cell Stemness and Fate.

Epicardial adipose tissues (EATs) and vascular tissues may both belong to the mesoepithelial lineage that develops from epicardium-derived progenitor cells (EPDCs) in developing and injured hearts. Very little is known of the molecular mechanisms of EPDC contribution in EAT development and neovascularization in adult heart, which the topic remains a subject of intense therapeutic interest and scientific debate. Here we studied the epigenetic control of stemness and anti-adipogenic and pro-vasculogenic fate of human EPDCs (hEPDCs), through investigating an angiogenic hormone, prokineticin-2 (PK2) signaling via its receptor PKR1. We found that hEPDCs spontaneously undergoes epithelial-to-mesenchymal transformation (EMT), and are not predestined for the vascular lineages. However, PK2 via a histone demethylase KDM6A inhibits EMT, and induces asymmetric division, leading to self-renewal and formation of vascular and epithelial/endothelial precursors with angiogenic potential capable of differentiating into vascular smooth muscle and endothelial cells. PK2 upregulates and activates KDM6A to inhibit repressive histone H3K27me3 marks on promoters of vascular genes (Flk-1 and SM22α) involved in vascular lineage commitment and maturation. In PK2-mediated anti-adipogenic signaling, KDM6A stabilizes and increases cytoplasmic ß-catenin levels to repress peroxisome proliferator-activated receptor-γ expression and activity. Our findings offer additional molecular targets to manipulate hEPDCs-involved tissue repair/regeneration in cardiometabolic and ischemic heart diseases. Stem Cells 2018;36:1589-1602.

Prokineticin receptor-1-dependent paracrine and autocrine pathways control cardiac tcf21+ fibroblast progenitor cell transformation into adipocytes and vascular cells.

Cardiac fat tissue volume and vascular dysfunction are strongly associated, accounting for overall body mass. Despite its pathophysiological significance, the origin and autocrine/paracrine pathways that regulate cardiac fat tissue and vascular network formation are unclear. We hypothesize that adipocytes and vasculogenic cells in adult mice hearts may share a common cardiac cells that could transform into adipocytes or vascular lineages, depending on the paracrine and autocrine stimuli. In this study utilizing transgenic mice overexpressing prokineticin receptor (PKR1) in cardiomyocytes, and tcf21ERT-creTM-derived cardiac fibroblast progenitor (CFP)-specific PKR1 knockout mice (PKR1 tcf-/-), as well as FACS-isolated CFPs, we showed that adipogenesis and vasculogenesis share a common CFPs originating from the tcf21+ epithelial lineage. We found that prokineticin-2 is a cardiomyocyte secretome that controls CFP transformation into adipocytes and vasculogenic cells in vivo and in vitro. Upon HFD exposure, PKR1 tcf-/- mice displayed excessive fat deposition in the atrioventricular groove, perivascular area, and pericardium, which was accompanied by an impaired vascular network and cardiac dysfunction. This study contributes to the cardio-obesity field by demonstrating that PKR1 via autocrine/paracrine pathways controls CFP-vasculogenic- and CFP-adipocyte-transformation in adult heart. Our study may open up new possibilities for the treatment of metabolic cardiac diseases and atherosclerosis.

Study of apoptosis-related interactions in colorectal cancer.

Abnormalities in apoptotic functions contribute to the pathogenesis of colorectal cancer. In this study, molecular interactions behind the apoptotic regulation have been explored. For this purpose, enrichment analysis was performed considering microRNAs (miRNAs) that putatively target TP53 and altered during colon cancer. This revealed gene associated with both TP53 and miRNAs. Further analysis showed that a significant molecular interaction between the shortlisted candidates (TP53, miR-143, KRAS, BCL2, and PLK1) exists. Mutation study was conducted to confirm the clinical relevance of candidates. It showed that the mutation extent does not significantly alter survival in patients thus making these candidates suitable as drug targets. Overall, we showed the importance of interactions between TP53, miR-143, KRAS, BCL2, and PLK1 with respect to colorectal cancer using bioinformatics approach.

Prokineticin receptor-1 signaling promotes Epicardial to Mesenchymal Transition during heart development.

The epicardium plays an essential role in coronary artery formation and myocardial development. However, signals controlling the developing epicardium and epicardial-mesenchymal transition (EMT) in the normal and diseased adult heart are studied less rigorously. Here we investigated the role of angiogenic hormone, prokineticin-2 and its receptor PKR1 in the epicardium of developing and adult heart. Genetic ablation of PKR1 in epicardium leads to partial embryonic and postnatal lethality with abnormal heart development. Cardiac developmental defects are manifested in the adult stage as ischemic cardiomyopathy with systolic dysfunction. We discovered that PKR1 regulates epicardial-mesenchymal transition (EMT) for epicardial-derived progenitor cell (EPDC), formation. This event affects at least three consequential steps during heart development: (i) EPDC and cardiomyocyte proliferation involved in thickening of an outer compact ventricular chamber wall, (ii) rhythmicity, (iii) formation of coronary circulation. In isolated embryonic EPDCs, overexpression or activation of PKR1 alters cell morphology and EMT markers via activating Akt signaling. Lack of PKR1 signal in epicardium leads to defective heart development and underlies the origin of congenital heart disease in adult mice. Our mice provide genetic models for congenital dysfunction of the heart and should facilitate studies of both pathogenesis and therapy of cardiac disorders in humans.

Prokineticin receptor 1 is required for mesenchymal-epithelial transition in kidney development.

Identification of factors regulating renal development is important to understand the pathogenesis of congenital kidney diseases. Little is known about the molecular mechanism of renal development and functions triggered by the angiogenic hormone prokineticin-2 and its receptor, PKR1. Utilizing the Gata5 (G5)-Cre and Wilms tumor 1 (Wt1)(GFP)cre transgenic lines, we generated mutant mice with targeted PKR1 gene disruptions in nephron progenitors. These mutant mice exhibited partial embryonic and postnatal lethality. Kidney developmental defects in PKR(G5-/-) mice are manifested in the adult stage as renal atrophy with glomerular defects, nephropathy, and uremia. PKR1(Wt1-/-) embryos exhibit hypoplastic kidneys with premature glomeruli and necrotic nephrons as a result of impaired proliferation and increased apoptosis in Wt1(+) renal mesenchymal cells. PKR1 regulates renal mesenchymal-epithelial transition (MET) that is involved in formation of renal progenitors, regulating glomerulogenesis toward forming nephrons during kidney development. In the isolated embryonic Wt1(+) renal cells, overexpression or activation of PKR1 promotes MET defined by the transition from elongated cell to octagonal cell morphology, and alteration of the expression of MET markers via activating NFATc3 signaling. Together, these results establish PKR1 via NFATc3 as a crucial modifier of MET processing to the development of nephron. Our study should facilitate new therapeutic opportunities in human renal disorders.-Arora, H., Boulberdaa, M., Qureshi, R., Bitirim, V., Messadeq, N., Dolle, P., Nebigil, C. G. Prokineticin receptor 1 is required for mesenchymal-epithelial transition in kidney development.

Mutation analysis of EGFR and its correlation with the HPV in Indian cervical cancer patients.

Cervical cancer is a major cause of morbidity and mortality particularly in developing countries. Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene is associated with increased sensitivity to tyrosine kinase inhibitors (TKIs). In this study, the presence of EGFR mutations in cervical cancer and its correlation with HPV were identified. EGFR mutations were found in 31 out of 95 patients (32.63 %). Results showed the presence of EGFR mutations in 5.263 % of patients in exon 19. In exon 20, mutations were predominant in 25.26 % patients. While in exon 21, 8.421 % of patients had mutations. HPV, which is associated with cervical cancer development, was found in 95.78 % (HPVL1), 92.63 % (HPV16), and 3.15 % (HPV18) of patients. No correlation was found between HPV16 and EGFR mutations (p = 0.0616). Overall, mutations like V742R, Q787Q, Q849H, E866E, T854A, L858R, E872Q, and E688Q were found. Next, impact of TKI inhibitor (gefitinib) was checked with respect to presence or absence of mutation considering Q787Q mutation in exon 20 (G/A genotype) which is present in 25.2 % patients. Mutated cervical cancer cell lines showed higher sensitivity to gefitinib. Overall, this study suggests the importance of mutations in EGFR gene and indicates their relevance with respect to TKIs treatment in Indian cervical cancer patients.

FL3, a Synthetic Flavagline and Ligand of Prohibitins, Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity.

AIMS: The clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flavaglines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxorubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated. METHODS AND RESULTS: Here, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimerization of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, suppresses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyocytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3. CONCLUSION: Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems.

EMT in cervical cancer: its role in tumour progression and response to therapy.

The prognosis of cervical patients significantly decreases as the cancer metastasizes to other parts of the body. The epithelial to mesenchymal transition (EMT) plays an important role in cervical cancer progression and metastasis. Recurrence is the primary cause of the increased number of deaths due to cervical cancer. Oncogenes, such as AEG1, Sam-68, FTS and miR-361-5p, induce EMT in cervical cancer. Tumour suppressors, such as LMX-1, SFRP1, klotho, and miR-155, suppress EMT in cervical cancer. Factors such as hypoxia, the radiation dose, cytokines, proteins, transcription factors, and signalling pathways also play an important role in the induction, progression and maintenance of EMT in cervical cancer. Overall, this review describes a wide range of factors with potential roles in EMT that have been identified to date, and this information could be important for the development of new and more effective therapeutics that ameliorate the negative impact of cervical pathogenesis via EMT.

miR-506 regulates epithelial mesenchymal transition in breast cancer cell lines.

Epithelial-mesenchymal transition (EMT) is an important parameter related to breast cancer survival. Among several microRNAs predicted to target EMT-related genes, miR-506 is a novel miRNA found to be significantly related to breast cancer patient survival in a meta-analysis. miR-506 suppressed the expression of mesenchymal genes such as Vimentin, Snai2, and CD151 in MDA-MB-231 human breast cancer cell line. Moreover, NF-κB bound to the upstream promoter region of miR-506 to suppress transcription. Overexpression of miR-506 inhibited TGFß-induced EMT and suppressed adhesion, invasion, and migration of MDA-MB-231 cells. From these results, we concluded that miR-506 plays a key role in the process of EMT through posttranslational control of EMT-related genes.

Coordinated regulation of ATF2 by miR-26b in γ-irradiated lung cancer cells.

MicroRNA regulates cellular responses to ionizing radiation (IR) through translational control of target genes. We analyzed time-series changes in microRNA expression following γ-irradiation in H1299 lung cancer cells using microarray analysis. Significantly changed IR-responsive microRNAs were selected based on analysis of variance analysis, and predicted target mRNAs were enriched in mitogen-activated protein kinase (MAPK) signaling. Concurrent analysis of time-series mRNA and microRNA profiles uncovered that expression of miR-26b was down regulated, and its target activating transcription factor 2 (ATF2) mRNA was up regulated in γ-irradiated H1299 cells. IR in miR-26b overexpressed H1299 cells could not induce expression of ATF2. When c-Jun N-terminal kinase activity was inhibited using SP600125, expression of miR-26b was induced following γ-irradiation in H1299 cells. From these results, we concluded that IR-induced up-regulation of ATF2 was coordinately enhanced by suppression of miR-26b in lung cancer cells, which may enhance the effect of IR in the MAPK signaling pathway.

miR-9 and let-7g enhance the sensitivity to ionizing radiation by suppression of NFκB1.

The activation of nuclear factor-kappa B1 (NFkB1) in cancer cells may confer resistance to ionizing radiation (IR). To enhance the therapeutic efficiency of IR in lung cancer, we screened for microRNAs (miRNAs) that suppress NFkB1 and observed their effects on radiosensitivity in a human lung cancer cell line. From time series data of miRNA expression in γ-irradiated H1299 human lung cancer cells, we found that the expression of miR-9 was inversely correlated with that of NFκB1. Overexpression of miR-9 down-regulated the level of NFκB1 in H1299 cells, and the surviving fraction of γ-irradiated cells was decreased. Interestingly, let-7g also suppressed the expression of NFκB1, although there was no canonical target site for let-7g in the NFκB1 3' untranslated region. From these results, we conclude that the expression of miR-9 and let-7g could enhance the efficiency of radiotherapy for lung cancer treatment through the inhibition of NFκB1.