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Background: Molecular classification of lung adenocarcinoma (LUAD) based on transcriptomic features has been widely studied. The complementarity of data obtained from multilayer molecular biology could help the LUAD classification via combining multi-omics information. Methods: We successfully divided samples from the The Cancer Genome Atlas (TCGA) (n=437) into four subtypes (CS1, CS2, CS3 and CS4) by 10 comprehensive multi-omics clustering methods in the “movics” R package. Meanwhile, external validation sets from different sequencing technologies proved the robustness of the grouping model. The relationship between subtypes, prognosis, molecular features, tumor microenvironment and response to first-line therapy was further analyzed. Next we used univariate Cox regression analysis and Lasso regression analysis to explore the application of biomarkers in clinical prognosis and constructed a prognostic model. Results: CS1 showed the worst overall survival (OS) among all four clusters, possibly related to its poor immune infiltration, higher tumor mutation and worse chromosomal stability. Patients in different subtypes differed significantly in cancer stem cell characteristics, activation of cancer-related pathways, sensitivity to chemotherapy and immunotherapy. The prognostic model showed good predictive performance. The 1-, 2- and 3-year areas under the curve of risk score were 0.779, 0.742 and 0.678, respectively. Seven genes (DKK1, TSPAN7, ID1, DLGAP5, HHIPL2, CD40 and SEMA3C) used to build the model may be potential therapeutic targets for LUAD. Conclusions: Four LUAD subtypes with different molecular characteristics and clinical implications were identified successfully through bioinformatic analysis. Our results may contribute to precision medicine and inform the development of rational clinical strategies for targeted and immune therapies.

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor and an oncogene product, which plays a pivotal role in tumor progression. Therefore, targeting persistent STAT3 signaling directly is an attractive anticancer strategy. The aim of this study is to test the efficacy of a novel STAT3 small molecule inhibitor, LLL12B, in suppressing medulloblastoma cells in vitro and tumor growth in vivo. LLL12B selectively inhibited the induction of STAT3 phosphorylation by interleukin-6 but not induction of STAT1 phosphorylation by INF-γ. LLL12B also induced apoptosis in human medulloblastoma cells. In addition, LLL12B exhibited good oral bioavailability in vivo and potent suppressive activity in tumor growth of medulloblastoma cells in vivo. Besides, combining LLL12B with cisplatin showed greater inhibition of cell viability and tumorsphere formation as well as induction of apoptosis comparing to single agent treatment in medulloblastoma cells. Furthermore, LLL12B and cisplatin combination exhibited greater suppression of medulloblastoma tumor growth than monotherapy in vivo. The present study supported that LLL12B is a novel therapeutic agent for medulloblastoma and the combination of LLL12B with a chemotherapeutic agent cisplatin may be an effective approach for medulloblastoma therapy.

Persistent STAT3 signaling is frequently detected in many cancer types including triple-negative breast cancer, and thus could potentially serve as a viable therapeutic target. We have designed a novel non-peptide compound LLY17 targeting STAT3 using Advanced Multiple Ligand Simultaneous Docking (AMLSD) methods. However, the efficacy of LLY17 has not been evaluated extensively in human and murine triple-negative breast cancer cells. In this study, we tested LLY17 in multiple human and murine triple-negative breast cancer cell lines. Human triple-negative breast cancer MDA-MB-468, MDA-MB-231, SUM159, and BT-549 cells, and murine triple-negative breast cancer 4T1 cells were used to study the inhibition effects of LLY17. The inhibition of STAT3 activation of LLY17 was investigated using western blot analysis. Cell viability, apoptosis and migration assays were carried out by MTT assay, Caspase-3/7 assay and wound healing assay, respectively. A mammary fat pad syngeneic mouse model was used to evaluate the antitumor effect of LLY17 in vivo. LLY17 inhibited IL-6-mediated induction of STAT3 phosphorylation but had no effect on IFN-γ-induced STAT1 phosphorylation or EGF-induced ERK phosphorylation. LLY17 inhibited STAT3 phosphorylation and induced apoptosis in human and murine triple-negative breast cancer cells but exhibited minimal toxicity toward Luminal A subtype breast cancer MCF-7 cells. RNAi attenuation experiments supported the requirement of STAT3 for LLY17-mediated inhibition of cell viability in triple-negative breast cancer cells. In addition, LLY17 inhibited cell migration of human and murine triple-negative breast cancer cells. Furthermore, LLY17 suppressed tumor growth and STAT3 phosphorylation of triple-negative breast cancer cells in a mammary fat pad syngeneic mouse model in vivo. Together, our findings suggest that targeting persistent STAT3 signaling by novel small molecule LLY17 may be a potential approach for the therapy of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has been ranked as one of the devastating malignancy worldwide. Its disease progression and treatment obstacle is associated with the negligible expression of estrogen receptors (ER−), progesterone receptors (PR−), and HER2 (HER2−). Due to a lack of growth hormone receptors, TNBC is desperately demanding effective therapeutic regimens. A growing body of evidence indicated that glycoprotein 130 kDa (GP130), the pivotal mediator involved in interleukin 6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) signaling pathways, is strongly correlated with tumor progression. Therefore, GP130 could become a novel target for treating TNBC. In our earlier studies, we demonstrated bazedoxifene as being a novel GP130 inhibitor. In the current report, anti-tumor effect of bazedoxifene on TNBC was further evaluated in TNBC cell lines SUM159, MDA-MB-231, and MDA-MB-468. We assessed anti-TNBC potency of bazedoxifene by carrying out various analysis encompassing western blot, cell proliferation, cell migration, colony formation, and growth of tumors in the xenograft mice. Our findings demonstrated that bazedoxifene not only decreased the expression of P-STAT3, IL-6/GP130-mediated downstream target genes P-AKT and P-ERK, but also blocked mitogen effects stimulated by IL-6, including cell viability, and overall cell survive, proliferation as well as cell migration. Likewise in laboratory animal model, tumor growth in mice was remarkably suppressed by bazedoxifene via an oral administration route. Combinational treatment of bazedoxifene plus the conventional chemotherapeutic agent, paclitaxel, synergistically impeded cell viability, colony formation, and cell migration far more significantly than the one from single-drug alone. Taken together, our data suggest that bazedoxifene may be developed as a promising small molecular therapeutic agent for eradicating TNBC intrinsically associated with constitutively active IL-6/GP130/STAT3 signaling cascade.

Background The Abramson technique for the correction of pectus carinatum (PC) is commonly performed worldwide. However, the postoperative complications of this technique related to bar fixation, including wire breakage and bar displacement, are relatively high. In this study, a new minimally invasive technique for correction of PC is described, in which the pectus bar is secured by bilateral selected ribs, and for which no special fixation to the rib is needed. Methods The procedure was performed by placing the pectus bar subcutaneously over the sternum with both ends of the bar passing through the intercostal space of the selected rib at the anterior axillary line. The protruding sternum was depressed by the bar positioned in this 2 intra- and 2 extra-thorax manners. Between October 2011 and September 2019, 42 patients with PC underwent this procedure. Results Satisfactory cosmetic results were obtained in all the patients. The mean operation time was 87.14 min, and the mean postoperative stay was 4.05 days. Wound infection occurred in 3 patients, 2 were cured by antibiotics, and 1 received bar removal 4 months after the initial operation due to the exposure of the implant resulting from uncontrolled infection. Mild pneumothorax was found in 3 patients and cured by conservative treatment. One patient suffered from hydropneumothorax, which was treated with chest drainage. The bars were removed at a mean duration of 24.4 months since primary repair in 20 patients without recurrence. Conclusions This new technique for minimally invasive correction of PC deformity is a safe and feasible procedure yielding good results and minimal complications.

Background: Uniportal video-assisted thoracic surgery (VATS) resections are of increasing interest in many thoracic surgery departments. With each experience in VATS lobectomy, we have incrementally improved the less invasive techniques in esophagectomy. Here, we report the preliminary results and feasibility of a modified McKeown procedure with uniportal thoracoscopy for upper or middle esophageal cancer in our institution. Methods: Between March 2015 and May 2016, modified uniportal McKeown procedure with uniportal thoracoscopy for upper or middle esophageal cancer was attempted in 44 patients in our institution. Results: Of the patients treated with uniportal thoracoscopy and laparoscopy, no patients were converted to open procedures, and all had a complete resection. The mean operative time was 408±34 min (range, 394–495 min). The mean thoracic operation was 163±16 min (range, 135–199 min). The mean blood loss was 245±102 mL (range, 100–450 mL). The mean number of lymph nodes resected was 24 (range, 14–36). The mean ventilator usage of the patients after surgery was 0.3±0.6 days, and the mean intensive care stay was 1.6 days (range, 1 to 7 days). The mean hospital stay was 11.8 days (range, 7 to 22 days). Major complications developed in 2 patients, both of whom had to undergo tracheotomy due to respiratory failure. No patients died of complications postoperatively, and none had clinically significant anastomotic leaks. Conclusions: Modified McKeown minimally invasive esophagectomy (MIE) with uniportal thoracoscopy seems to be a feasible option for patients with upper or middle esophageal cancer. Larger studies with longer follow-up are needed to further investigate this approach.

Background/aim Interleukin-6 (IL-6) and interleukin-8 (IL-8) play important roles in the progression of triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC). This is the first experiment to combine small molecules targeting these two signaling pathways to treat TNBC and PDAC cells. Materials and methods Cell viability, colony formation and cell migration assays were conducted when TNBC or PDAC cells were treated with bazedoxifene (targeting IL-6) or reparixin/SCH527123 (targeting IL-8) or their combination. Results The combined treatment had a more potent inhibition of cell viability, colony formation and cell migration than monotherapy in TNBC and PDAC cells. The results also showed that the combination of bazedoxifene with SCH527123 seemed to be more effective than that with reparixin in inhibiting cell viability and colony formation of TNBC. Conclusion Novel drug combinations of bazedoxifene and reparixin, as well as bazedoxifene and SCH527123 may provide more effective treatments for TNBC and PDAC.

IFN-γ plays a crucial role in anti-tumor responses and also induces expression of PD-L1, a well-established inhibitor of anti-tumor immune function. Understanding how molecular signaling regulates the function of IFN-γ might improve its anti-tumor efficacy. Here, we show that the tumor expression of IFN-γ expression alone has no significant prognostic value in patients with locally advanced lung adenocarcinoma. Surprisingly, patients with tumors expressing both IFN-γ and PD-L1 have the best prognosis compared to those with tumors expressing IFN-γ or PD-L1 alone. Transcriptome analysis demonstrated that tumor tissues expressing IFN-γ display gene expression associated with suppressed cell cycle progression and expansion. Unexpectedly this profile was observed in PD-L1+ but not PD-L1- tumors. The current concept is that PD-L1 functions as a shield protecting tumor cells from cytolytic T cell (CTL)-mediated anti-tumor progression. However, our data indicate that PD-L1 expression in the presence of IFN-γ might serve as biomarker for the sensitivity of tumors to the inhibitory effect of IFN-γ. Mechanistic analysis revealed that in lung adenocarcinoma cells IFN-γ-induced activation of JAK2-STAT1 and PI3K-AKT pathways. The activation of JAK2-STAT1 is responsible for the anti-proliferative effect of IFN-γ. Inhibition of PI3K downregulated PD-L1 expression and enhanced the anti-proliferative effect of IFN-γ, suggesting that blockade of PI3K might maximize the IFN-γ-mediated anti-tumor effect. Our findings provide evidence for crosstalk between JAK2-STAT1 and PI3K-AKT pathways in response to IFN-γ in lung adenocarcinoma and have implications for the design of combinatorial targeted therapy and immunotherapy for the treatment of lung adenocarcinoma.

Since the development of the uniportal video-assisted thoracoscopic surgery (VATS) technique, the use of uniportal VATS has become increasingly popular for the surgical resection of non-small cell lung cancer (NSCLC). The objective of this study is to introduce a novel modularly designed surgical pattern for uniportal VATS for lung cancer resection and to investigate the safety, feasibility, and efficacy of this novel method.The clinical data of NSCLC patients who underwent a curative uniportal VATS lobectomy between March 2015 and April 2016, including via the modular pattern (MP) and the conventional pattern (CP), were retrospectively collected and analyzed. Perioperative and postoperative parameters, including the operation duration, estimated intraoperative blood loss, rate of conversion to thoracotomy, lymph node dissection number, and postoperative complications, were compared between the two groups.A total of 321 patients were identified, among whom 221 underwent MP uniportal VATS lobectomy and 100 were treated via CP uniportal VATS lobectomy. Patients in the MP group experienced a shorter operation duration (135.58 ± 47.16 minutes versus 148.86 ± 42.53 minutes, P = .017) and less estimated intraoperative blood loss (75.20 ± 37.99 mL versus 89.50 ± 41.11 mL, P = .003) than patients in the CP group. No significant difference was observed in the intraoperative conversion rate (2.7% versus 5.0%, P = .477), total number of lymph nodes dissected (24.67 ± 7.73 versus 25.34 ± 7.62, P = .471), postoperative drainage duration (4.86 ± 1.96 days versus 4.78 ± 2.10 days, P = .755), length of stay (9.60 ± 2.93 days versus 9.97 ± 2.80 days, P = .286), or incidence of postoperative complications between the two groups. No postoperative deaths occurred.MP uniportal VATS lobectomy combined with mediastinal lymphadenectomy appears to be a safe and feasible technique for the treatment of NSCLC. The use of this technique can reduce the operation duration and intraoperative blood loss.

Persistent STAT3 signaling is frequently detected in many cancer types including triple-negative breast cancer, and thus could potentially serve as a viable therapeutic target. We have designed a novel non-peptide compound LLY17 targeting STAT3 using Advanced Multiple Ligand Simultaneous Docking (AMLSD) methods. However, the efficacy of LLY17 has not been evaluated extensively in human and murine triple-negative breast cancer cells. In this study, we tested LLY17 in multiple human and murine triple-negative breast cancer cell lines.Human triple-negative breast cancer MDA-MB-468, MDA-MB-231, SUM159, and BT-549 cells, and murine triple-negative breast cancer 4T1 cells were used to study the inhibition effects of LLY17. The inhibition of STAT3 activation of LLY17 was investigated using western blot analysis. Cell viability, apoptosis and migration assays were carried out by MTT assay, Caspase-3/7 assay and wound healing assay, respectively. A mammary fat pad syngeneic mouse model was used to evaluate the antitumor effect of LLY17 in vivo.LLY17 inhibited IL-6-mediated induction of STAT3 phosphorylation but had no effect on IFN-γ-induced STAT1 phosphorylation or EGF-induced ERK phosphorylation. LLY17 inhibited STAT3 phosphorylation and induced apoptosis in human and murine triple-negative breast cancer cells but exhibited minimal toxicity toward Luminal A subtype breast cancer MCF-7 cells. RNAi attenuation experiments supported the requirement of STAT3 for LLY17-mediated inhibition of cell viability in triple-negative breast cancer cells. In addition, LLY17 inhibited cell migration of human and murine triple-negative breast cancer cells. Furthermore, LLY17 suppressed tumor growth and STAT3 phosphorylation of triple-negative breast cancer cells in a mammary fat pad syngeneic mouse model in vivo.Together, our findings suggest that targeting persistent STAT3 signaling by novel small molecule LLY17 may be a potential approach for the therapy of triple-negative breast cancer.

Ovarian cancer is one of the most lethal cancer types in American women. The platinum agent cisplatin, and/or paclitaxel, remains the first‑line chemotherapy for ovarian cancer, but the treatment success is severely limited by chemoresistance. As previously reported, persistent STAT3 signaling is associated with resistance to cisplatin and paclitaxel. To investigate whether the STAT3 small molecule inhibitor LLL12 can enhance the treatment effect of cisplatin and paclitaxel in ovarian cancer cells, A2780, SKOV3, CAOV‑3 and OVCAR5 cells were treated with LLL12, cisplatin and paclitaxel, alone or combination, and cell viability, cell migration, cell growth and protein expression levels were then evaluated. It was found that, for all four human ovarian cancer cell lines, STAT3 phosphorylation was significantly inhibited by LLL12. The combined treatment of LLL12 with paclitaxel or LLL12 with cisplatin exerted significantly greater inhibition of cell viability, cell migration and cell growth than did monotherapy. In addition, LLL12 and cisplatin in combination, or the three drugs in combination, also led to greater inhibition of cell viability and cell migration than combined cisplatin and paclitaxel treatment, a standard treatment for ovarian cancer. The present results demonstrated that the STAT3 small molecule inhibitor LLL12 is a potent inhibitor of STAT3 phosphorylation, cell viability and migration in human ovarian cancer cells. Combining LLL12 with cisplatin or paclitaxel may be a viable therapeutic approach in the treatment of patients with ovarian cancer exhibiting persistent STAT3 signaling.

Uniportal video-assisted thoracoscopic lobectomy for non-small-cell lung cancer is accepted worldwide, with incisions ranging from 4 to 6 cm. We believed in less invasive and more precise that uniportal video-assisted thoracoscopic lobectomy could be. Therefore, we performed modular uniportal thoracoscopic lobectomy with systemic lymphadenectomy on left upper lobe using a 3-cm-diameter port. And the modular surgical route was arranged in seven modules. Anesthesia, patient positioning and instruments play an important role in the surgery. From October 2014 to June 2015, 96 patients underwent this modular surgery and all patient were discharged uneventfully with no postoperative deaths. Compared with multi-port VATS, the operation time were longer than multiport video-assisted thoracoscopic surgery (VATS) (164.70±12.50 vs. 160.70±11.60 min, P>0.05), and the mean lymphadenectomy station was 6.00±0.77, and the mean lymphadenectomy number was 17.58±5.33. There is no significant difference on lymphadenectomy. Thus, modular uniportal video-assisted thoracoscopic lobectomy with systemic lymphadenectomy on left upper lobe using a 3-cm-diameter port is a safe, feasible, and less painful technique for select patients with lung disease.

Systemic immune-inflammation index (SII), based on lymphocyte (L), neutrophil (N), and platelet (P) counts, was recently developed and reflects comprehensively the balance of host inflammatory and immune status. We explored its prognostic value in localized gastric cancer (GC) after R0 resection and the potential associations with Thymidine phosphorylase (TYMP), which was reported to increase the migration and invasion of gastric cancer cells. A total of 455 GC patients who received D2 gastrectomy were enrolled. Blood samples were obtained within 1 week before surgery to measure SII (SII = P × N/L). TYMP expression was measured on tumor sections by immunohistochemical analysis. Preoperative high SII indicated worse prognosis (HR: 1.799; 95% CI: 1.174-2.757; p = 0.007) in multivariate analysis and was associated with higher pathological TNM stage, deeper local invasion of tumor and lymph node metastasis (all p < 0.001). SII predicted poor overall survival in pathological TNM stage I subgroup also (p < 0.001). Furthermore we found that in high SII group, positive rate of TYMP expression increased (53.7% vs 42.7%, p = 0.046) and TYMP positive patients had higher SII score (median 405.9 vs. 351.9, p = 0.026). SII, as a noninvasive and low cost prognostic marker, may be helpful to identify higher-risk patients after R0 resection, even for stage I GC patients.

UGT1A1*28/*6 as predictors of severe irinotecan-related diarrhea (SIRD) were duplicated by many studies. However, some patients of lower risk genotype (UGT1A1*1/*1) still suffered SIRD and the extremely low frequency of UGT1A1*6/*6 limited its clinical usage. Previous studies proved that the transforming growth factor (TGFB) family may have some effect on MTX-induced mucositis. However, the associations between TGFB gene variants and SIRD have never been reported so far. Our aim was to improve the predictive value of UGT1A1 gene variants on SIRD. Six SNPs (TGFB1 rs1800469; TGFBR1 rs10733710, rs334354 and rs6478974; TGFBR2 rs3087465; UGT1A1*6) and UGT1A1*28 were selected for genotyping in 160 metastatic colorectal cancer patients treated with irinotecan in a prospective multicenter trial (NCT01282658). UGT1A1*6, UGT1A1*28, rs1800469 and rs3087465 were all associated with SIRD (p = 0.026, 0.014, 0.047 and 0.045 respectively). A novel genetic score model (with a cut off value of 1.5) based on them was created to predict SIRD (OR = 11.718; 95 % CI 2.489–55.157, p = 0.002). In patients of gene score > 1.5, the risk of SIRD was much higher (23.5 vs. 2.8 %, p = 2.24E−04) and continued in the first 6 cycles of chemotherapy, while in patients with gene score ≤1.5, the risk was much lower and none of them suffered SIRD after the first cycle of chemotherapy (p = 0.0003). The novel genetic score model improved the predictive value of UGT1A1 on SIRD. If validated, it will provide valuable information for clinical use of irinotecan.

Persistent STAT3 signaling is frequently detected in many cancer types and thus could potentially serve as a viable therapeutic target. In this study, we tested two novel small STAT3 inhibitors, LLY17 and LLL12B in triple-negative breast cancer cells, which frequently express persistent STAT3 phosphorylation. LLY17 and LLL12B selectively inhibited IL-6-mediated induction of STAT3 phosphorylation but no effect on IFN-γ mediated induction of STAT1 phosphorylation. LLY17 and LLL12B induced apoptosis in triple-negative breast cancer cells but exhibited minimal toxicity toward normal mammary epithelial cells. RNAi attenuation experiments confirmed the requirement of STAT3 for LLY17 and LLL12B-mediated inhibition of cell viability in triple-negative breast cancer cells. LLY17 and LLL12B inhibited STAT3 phosphorylation in human and murine triple-negative breast cancer cells. In addition, LLY17 and LLL12B inhibited cell migration of human and murine triple-negative breast cancer cells. Furthermore, LLY17 and LLL12B suppressed tumor growth and STAT3 phosphorylation of triple-negative breast cancer cells in vivo in a mammary fat pad murine syngeneic mouse model. Together, our findings suggest that targeting persistent STAT3 signaling pathway by novel oral bioavailable small molecules LLY17 and LLL12B may be a potential approach for the therapy of triple-negative breast cancer. Citation Format: Li Pan, Xiang Chen, Shengling Fu, Chenglong Li, Hui-Wen Lo, Jiayuh Lin. Novel small molecule STAT3 inhibitors induce apoptosis and suppress cell migration and tumor growth in triple-negative breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-11.

Breast cancer, especially triple-negative breast cancer (TNBC), has limited treatment options. We repurposed the FDA-approved drug bazedoxifene as a novel inhibitor of interleukin 6/glycoprotein 130 signaling. In this study, we investigated the inhibitory effects of bazedoxifene alone or in combination with paclitaxel on several estrogen receptor positive and TNBC cells. Bazedoxifene inhibited the cell viability of these cells, as well as tumor growth of TNBC cells in a xenograft tumor model. Furthermore, bazedoxifene combined with paclitaxel exhibited more potent inhibition of cell viability, colony formation, and cell migration and induced more apoptosis in vitro, and generated stronger inhibition of tumor growth of TNBC in vivo than either drug alone. Western blotting showed that bazedoxifene inhibited estrogen receptor positive breast cancer cells by suppressing the expression of estrogen receptor, Cyclin D1, p-P70S6K, Survivin, c-Myc, and Bcl-2, and bazedoxifene inhibited TNBC cells by inhibiting the expression of phosphorylated STAT3 (Tyr705), Cyclin D1, p-P70S6K, c-Myc, p-AKT (Ser473) and p-ERK 1/2 (T202/Y 204) without changing the expression of total STAT3. When combined with paclitaxel, bazedoxifene may be a potential small molecule for the treatment of both estrogen receptor positive and triple-negative breast cancer.

Following publication of their article, the authors noticed that there were minor errors in Figs. 3, 7 and S5. The errors had no effect on the scientific content or conclusions. The rectified figures are given below.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR‑TKIs) have revolutionized the treatment of patients with advanced EGFR-mutant NSCLC. However, drug resistance eventually develops in the majority of patients despite an excellent initial response. The present study aimed to investigate the mechanism of acquired resistance to EGFR-TKIs and to explore strategies to overcome the resistance to EGFR-TKIs from a gender perspective. PC9 and Hcc827 cell lines, sensitized to EGFR-TKI, and secondary TKI-resistant PC9-ER (erlotinib resistant) and Hcc827-ER cell lines were evaluated for the expression of ERβ1. The proliferative ability of both cell lines was analyzed after transfection of siRNA-ERβ1 using Cell Counting Kit-8 and colony formation assays. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and Akt activation were detected. The co-inhibition efficiency of erlotinib and fulvestrant was analyzed in PC9-ER xenografts. The expression of ERβ1 was investigated in tumor tissues of EGFR-TKI-treated patients, and its correlation with clinicopathological factors and progression-free survival (PFS) was assessed. The expression of ERβ1 was upregulated secondary to EGFR-TKIs in PC9 and Hcc827 cell lines, with β-estradiol dependence. Both PC9-ER and Hcc827-ER cell lines were re-sensitized to erlotinib after downregulation of the expression of ERβ1. ERK1/2 and Akt pathways were activated following the silencing of the expression of ERβ1 in PC9-ER and Hcc827 cell lines. The co-treatment of erlotinib and fulvestrant exhibited better growth inhibitory efficiency compared with the treatment of each agent alone in PC9-ER-derived xenografts. Primary NSCLC samples of 53 patients treated with EGFR-TKIs were analyzed. ERβ1 was highly expressed, and the strong expression of cytoplasmic ERβ1 was related to a shorter PFS. In conclusion, ERβ1 was activated in EGFR-TKI secondary resistance. The downregulation of ERβ1 sensitized the cells to EGFR-TKIs. ERβ1 may be a key molecule in EGFR-TKI therapy. In addition, anti-ERβ1 treatment may reverse TKI resistance.

// Zun-yi Zhang 1 , Sheng-ling Fu 1 , Su-qin Xu 2 , Xiao Zhou 2 , Xian-shen Liu 2 , Yong-jian Xu 2 , Jian-ping Zhao 2 , Shuang Wei 2 1 Department of Surgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan 430030, China 2 Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan 430030, China Correspondence to: Shuang Wei, e-mail: wsdavid2001@163.com Keywords: hsa-miR-526b, Ku80, microRNA, NSCLC, p53 Received: August 24, 2014 Accepted: November 24, 2014 Published: December 22, 2014 ABSTRACT Ku80 is involved in DNA double-strand breaks (DSBs) repair. Ku80 is overexpressed in lung cancer tissues, yet, molecular mechanisms have not been examined. We identified that miRNA, hsa-miR-526b, is bound to the 3’-UTR of Ku80 mRNA, thus decreasing Ku80 expression in NSCLC cells. Hsa-miR-526b was downregulated in NSCLC tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Overexpression of Ku80 and downregulation of hsa-miR-526b were associated with poor clinical outcomes of NSCLC patients. Hsa-miR-526b suppressed NSCLC cell proliferation, clonogenicity, and induced cell cycle arrest and apoptosis. Hsa-miR-526b inhibited xenografts and orthotopic lung tumor growth. Further, Ku80 knockdown in NSCLC cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-526b overexpression. In agreement, Ku80 restoration partially reversed cell cycle arrest and apoptosis induced by hsa-miR-526b in NSCLC cells in vitro and in vivo . In addition, hsa-miR-526b overexpression or Ku80 knockdown increased p53 and p21 CIP1/WAF1 expression. These findings reveal that hsa-miR-526b is a potential target in cancer therapy.

Interactions between interleukin (IL)-8 and its receptors, C‑X-C chemokine receptor 1, (CXCR1) and CXCR2 serve crucial roles in increasing cancer progression. Inhibition of this signaling pathway has yielded promising results in a number of human cancers, including breast, melanoma and colon. However, the effects of CXCR1/2 antagonist treatment on pancreatic cancer remain unclear. The present study aimed to demonstrate that treatment with the clinical grade CXCR1/2 antagonist, reparixin, or the newly discovered CXCR1/2 antagonist, SCH527123, may result in a reduction of the malignant features associated with this lethal cancer. The effects of reparixin or SCH527123 exposure on human pancreatic cancer cell lines BxPC‑3, HPAC, Capan‑1, MIA PaCa‑2, and AsPC‑1 were examined in regard to cell proliferation, cell viability, colony formation and migration. The effects of CXCR1/2 inhibition on the protein expression of well-known downstream effectors, including phosphorylated (p)-signal transducer and activator of transcription 3 (STAT3), p‑RAC‑α serine/threonine-protein kinase (p‑AKT), p‑extracellular signal-regulated kinase (p‑ERK1/2) and p‑ribosomal protein S6 (p‑S6), were assessed by western blotting assays. The effects of IL‑8 signaling on the proliferative activities intrinsic to the human pancreatic cancer cell lines Capan‑1, AsPC‑1 and HPAC were examined by bromodeoxyuridine assay. Treatment with either reparixin or SCH527123 yielded dose-dependent growth suppressive effects on HPAC, Capan‑1 and AsPC‑1 cells that may have otherwise undergone robust proliferation upon IL‑8 stimulation. In addition, reparixin or SCH527123 treatment inhibited CXCR1/2-mediated signal transduction, as demonstrated by the decreased phosphorylation levels of effector molecules STAT3, AKT, ERK and S6 that are downstream of the IL‑8/CXCR1/2 signaling cascade in HPAC cells. These data were in close agreement with the reduced cell migration and colony formation. Results from the present study suggested that reparixin and SCH527123 may be promising therapeutic agents for the treatment of pancreatic cancer by inhibiting the IL‑8/CXCR1/2 signaling cascade.

Estrogens are key signaling molecules that regulate various physiological processes such as cell growth, development, and differentiation. They also play a major role in many pathological conditions, such as hormone-dependent cancer. The importance of inhibiting estrogen receptor signaling in diseases of estrogen target tissues, such as breast cancer, is well documented. However, the role of estrogen signaling in diseases of nontarget tissues, such as lung cancer, is not well characterized. The aim of the current study is to examine the expression of estrogen receptor (ER) and the roles of estradiol (E2) and fulvestrant on the progression of lung cancer. Tissue microarray (TMA) and immunohistochemistry (IHC) analyses were used to detect the expression of aromatase, ER, and ER in 198 patients. We performed analyses to determine if there was any correlation among these three proteins. A mouse model of urethane-induced lung adenocarcinoma was used in the study. Mice were divided into three treatment groups: blank control, E2 alone, and E2 + fulvestrant (ER antagonist). Western blot analysis and fluorescence quantitative PCR (FQ-PCR) were used to measure expression of ER protein and mRNA levels, respectively. ER, but not ER, was overexpressed in NSCLC samples. Lung cancer progression in mice treated with E2 was significantly increased compared to either the control group or the E2 + fulvestrant group. Mice in the E2 treatment group had significantly increased expression of ER at both the mRNA and protein levels compared to mice treated with E2 + fulvestrant or control. Our data suggest that ER promotes lung cancer progression in mice and that this progression can be inhibited with fulvestrant. These findings may help elucidate the role of ER in lung cancer and suggest that estrogen receptor antagonists, such as fulvestrant, may be therapeutically beneficial for the treatment of the disease.

Epidermal growth factor receptor (EGFR) mutation status is the best predictor of patient response to treatments with tyrosine kinase inhibitors in primary lung adenocarcinoma and is typically analyzed by DNA-based techniques, such as direct DNA sequencing and allele-specific PCR. Recently, however, two mutation-specific antibodies against delE746-A750 in exon 19 and L858R in exon 21 have opened the door for a more convenient and more efficient strategy to determine EGFR mutation status. To evaluate the clinical application of a new mutation-specific mouse monoclonal antibody for EGFR (L858R), we performed immunohistochemistry (IHC) studies with tumor samples from primary lung adenocarcinoma in retrospective and validation settings. A total of 215 cases of primary lung adenocarcinoma were examined and compared using a combination of DNA-based techniques (direct DNA sequencing and/or allele-specific PCR) and protein-based IHC. IHC staining was assessed on a 0 to 3+ score scale, and a cutoff value of 2+ was used as positive by IHC. In the retrospective setting, statistical analyses of the data showed that the sensitivity of IHC was 90.9 % and the specificity was 96.8 %. Findings from the validation study demonstrated that the sensitivity and specificity of IHC were 88.2 % and 100 %, respectively. IHC with the novel mutation-specific antibody could be used as a screening method to assess the EGFR L858R mutation status in primary lung adenocarcinoma.

OBJECTIVES Lung-preserving surgery was proved to be effective and safe to treat patients with benign bronchial strictures. However, this surgical treatment has been rarely reported in patients with complete occlusion in the left main bronchus. The aim of this study was to assess the value of this procedure and report our experience in the treatment of these patients with left atelectasis caused by inflammatory bronchial occlusion. METHODS We reviewed and analysed the medical records of 8 patients who had undergone left main bronchus sleeve resection for symptomatic left atelectasis caused by inflammatory bronchial occlusion from May 2007 to April 2011. RESULTS Eight patients (3 men and 5 women) with a medical history of active pulmonary tuberculosis were involved in this study. The median age was 23 years. Parenchyma-sparing left main bronchus resection was performed in 4 patients, 1 of whom received partial wedge resection in the lingual lobe. Left main bronchus sleeve resection plus superior lobectomy was performed in 2 patients and left main bronchus sleeve resection plus left inferior lobectomy in 2 patients, 1 of whom received additional partial wedge resection of the lingual lobe. The procedure was completed successfully in all 8 patients without postoperative deaths. The mean follow-up time was 49.3 months, ranging from 23 to 69 months. No major complications, including stenosis and atelectasis, were observed during the follow-up period. The symptoms of pulmonary atelectasis disappeared and pulmonary ventilation function improved significantly. CONCLUSIONS In symptomatic patients with left atelectasis caused by inflammatory bronchial occlusion, lung-preserving surgery is an effective and safe surgical treatment.

Insulin-like growth factors (IGFs), along with their receptors and binding proteins, play key roles in human cell proliferation, differentiation and apoptosis. There is now substantial evidence suggesting that the IGF system is involved in the pathogenesis and progression of various malignancies. Recent studies have shown that targeting of the IGF-1 receptor (IGF-1R) signaling pathway might be a novel approach for the treatment of cancer. Presently numerous agents featuring different mechanisms of IGF targeting methods such as IGF-1R monoclonal antibodies, IGF-1R tyrosine kinase inhibitors and IGF ligand specific antibodies are being investigated in more than 170 clinical trials and appear to have potential therapeutic efficacy. However, advanced trials reiterate the importance of predictive biomarkers to guide the clinical efforts of these agents. As a result, current research strategies are emerging to identify the most suitable subpopulations of patients that might benefit from these treatments. Furthermore, newly presented toxicity and growth hormone response and implication of hybrid receptors in IGF signaling pathway pose unprecedented challenges in the design and application of anti-IGF agents. On the other hand, cross-talk in downstream signaling between IGF-1R and other tumor promoting pathways and the development of multi-target agents might encourage the IGF-1R-targeted therapies further into comprehensive treatments of cancer. With both challenges and prospects ahead, this paper reviewed the progress in this particular field.

Estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF-1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. LADE was induced with urethane in ovariectomized Kunming mice. Tumor-bearing mice were divided into seven groups: 17β-estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024 (IGF-1 inhibitor), E2+IGF-1, E2+IGF-1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ERα/ERβ, IGF-1, IGF-1R and Ki67 was examined using tissue-microarray-immunohistochemistry, and IGF-1, p-ERβ, p-IGF-1R, p-MAPK and p-AKT levels were determined based on Western blot analysis. Fluorescence-quantitative polymerase chain reaction was used to detect the mRNA expression of ERβ, ERβ2 and IGF-1R. Tumors were found in 93.88% (46/49) of urethane-treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF-1 group, tumor growth was significantly higher than in the E2 group (p < 0.05), the IGF-1 group (p < 0.05) and control group (p < 0.05). Similarly, the expression of ERβ, p-ERβ, ERβ2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT and Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p < 0.05). This study demonstrated for the first time that estrogen and IGF-1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ERβ1, ERβ2 and IGF-1R play important roles.

Insulin-like growth factor-I (IGF-I) is a mitogenic and anti-apoptotic factor. Serum IGF-I concentration is related to some cancer risk and tumor progression. The aim of this research was to study the association of preoperative serum IGF-I concentration with clinicopathological parameters and prognosis of non-small cell lung cancer (NSCLC). Preoperative serum IGF-I concentration was measured in 80 consecutive patients with NSCLC who underwent radical lung cancer resection, and 45 patients with benign pulmonary lesion (BPL) by using enzyme linked immunosorbent assay (ELISA). The results showed that the serum IGF-I concentration was elevated and correlated with clinicopathological parameters and overall survival (OS) in NSCLC patients. Serum IGF-I concentration was significantly higher in patients with NSCLC than in those with BPL. The IGF-I concentrations were significantly higher in NSCLC patients with ≥T2, N1-3, and in IIIA-IV but not in those with

Triple-negative breast cancer (TNBC) is a major cause of death among breast cancer patients and is the only subtype of breast cancer that is still lacking effective therapeutic options. IL-6 is one of the principal oncogenic mediators in breast cancer and systemic IL-6 levels correlates with poor prognosis, advanced disease, and metastases. Importantly, growth of TNBC cells are replied on autocrine cytokines including IL-6 and TNBC cells secret the highest levels of IL-6 comparing to other subtypes of breast cancer. Therefore, IL-6 signaling represents a novel approach with a potential to improve the therapeutic efficacy. To date, however, no small molecules that target IL-6 signaling are available for clinical cancer therapy. IL-6 binds to IL-6 Rα, then recruits Glycoprotein 130 (GP130) to form hexamer consisting two IL-6/IL-6 Rα/GP130 heterotrimers to trigger a signaling cascade downstream including JAK/STAT3, PI3-K/AKT/mTOR, and MEK/ERK. Therefore, it is possible to target IL-6 signaling by blocking IL-6 binds to GP130 or IL-6 Rα and thus inhibiting its signaling cascade downstream. We have utilized a novel drug discovery approach combining Multiple Ligand Simultaneous Docking and drug repurposing to target GP130 and have identified a FDA-approved drug Bazedoxifene (for the prevention of the osteoporosis in postmenopausal women) with a novel function to inhibit IL-6 and GP130 proteinprotein interactions and thus blocking IL-6 signaling cascade downstream. In this study, we examined the therapeutic efficacy of Bazedoxifene in combination with paclitaxel on human TNBC cells and TNBC tumor model, aiming to provide experimental results of Bazedoxifene and paclitaxel combination for TNBC therapy. Our data showed Bazedoxifene inhibited increased STAT3 phosphorylation induced by IL-6. Bazedoxifene also inhibited phosphorylation of STAT3, AKT, and ERK in TNBC cells that produced IL-6. In addition, combination of Bazedoxifene with paclitaxel exhibited more significant inhibition on cell viability and colony formation and induction of apoptosis than single agent alone in TNBC cells in vitro. Moreover, Bazedoxifene inhibits cell migration and combination of Bazedoxifene with paclitaxel more significantly inhibit cell migration than single agent alone. We also showed bazedoxifene could inhibit increased proliferation of TNBC cells induced by IL-6. The combination of Bazedoxifene with paclitaxel also showed significantly inhibition of tumor growth of TNBC in vivo furtherly supported the therapeutic effects of Bazedoxifene. The results support the significant therapeutic efficacy of Bazedoxifene and paclitaxel combination for further TNBC therapy. Citation Format: Xiang Chen, Shengling Fu, Jilai Tian, Yang Cao, Chenglong Li, Jiayuh Lin. Repurposing FDA-approved drug bazedoxifene as a novel inhibitor of IL-6 signaling for triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 864.

The αvβ6 integrin is a cell surface adhesion molecule that plays critical roles in the injury and inflammation processes. We hypothesized that polymorphisms in αvβ6 integrin genes (ITGAV and ITGB6) might be associated with the risk of radiation pneumonitis (RP) in lung cancer patients treated with thoracic radiation. We genotyped three potentially functional αvβ6 integrin single-nucleotide polymorphisms (rs1839123 and rs4129787 in ITGAV, and rs4665162 in ITGB6) and found that the genotypes of rs4665162 single-nucleotide polymorphisms were predictors of RP development (for grade ≥2 RP, HR = 1.505, 95 % CI 1.069–2.119, P = 0.019; for grade ≥3 RP, HR = 3.006, 95 % CI 1.431–6.313, P = 0.004). Our results showed that AG/GG genotypes of ITGB6 rs4665162 gene were associated with a higher risk of RP in patients with lung cancer receiving radiotherapy and thus may serve as a reliable predictor of RP. Further studies will be needed to confirm these findings.

The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have been increasingly recognized to drive the development of malignancies, including non-small cell lung cancer (NSCLC). This study aimed to investigate the effects of IGF-1R and its inhibitor, AG1024, on the progression of lung cancer. Tissue microarray and immunohistochemistry were employed to detect the expressions of IGF-1 and IGF-1R in NSCLC tissues (n=198). Western blotting was used to determine the expressions of IGF-1 and phosphorylated IGF-1R (p-IGF-1R) in A549 human lung carcinoma cells, and MTT assay to measure cell proliferation. Additionally, the expressions of IGF-1, p-IGF-1R and IGF-1R in a mouse model of lung cancer were detected by Western blotting and real-time fluorescence quantitative polymerase chain reaction (FQ-PCR), respectively. The results showed that IGF-1 and IGF-1R were overexpressed in NSCLC tissues. The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1+AG1024 or untreated cells. In the presence of IGF-1, the proliferation of A549 cells was significantly increased. The progression of lung cancer in mice treated with IGF-1 was significantly increased as compared to the group treated with IGF-1+AG1024 or the control group, with the same trend mirrored in IGF-1/p-IGF-1R/IGF-1R at the protein and/or mRNA levels. It was concluded that IGF-1 and IGF inhibitor AG1024 promotes lung cancer progression.

Our previous study revealed that Ku80 was overexpressed in lung cancer tissues and hsa-miR-623 regulated the Ku80 expression; however, the detailed function of hsa-miR-623 in lung cancer was unclear. We identified that hsa-miR-623 bound to the 3'-UTR of Ku80 mRNA, thus significantly decreasing Ku80 expression in lung adenocarcinoma cells. Hsa-miR-623 was downregulated in lung adenocarcinoma tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Downregulation of hsa-miR-623 was associated with poor clinical outcomes of lung adenocarcinoma patients. Hsa-miR-623 suppressed lung adenocarcinoma cell proliferation, clonogenicity, migration and invasion in vitro. Hsa-miR-623 inhibited xenografts growth and metastasis of lung adenocarcinoma in vivo. Ku80 knockdown in lung adenocarcinoma cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-623 overexpression. Further, hsa-miR-623 overexpression decreased matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels, with decreased ERK/JNK phosphorylation. Inhibition of hsa-miR-623 or overexpression of Ku80 promoted lung adenocarcinoma cell invasion, activated ERK/JNK phosphorylation and increased MMP-2/9 expressions, which could be reversed by ERK kinase inhibitor or JNK kinase inhibitor. In summary, our results showed that hsa-miR-623 was downregulated in lung adenocarcinoma and suppressed the invasion and metastasis targeting Ku80 through ERK/JNK inactivation mediated downregulation of MMP-2/9. These findings reveal that hsa-miR-623 may serve as an important therapeutic target in lung cancer therapy.

Despite undergoing curative resection, the 5-year survival rate for stage III non-small cell lung cancer (NSCLC) patients is less than 25%. There is a need for biomarkers for prediction of survival and guiding individual therapy. MiR-155 is one of most commonly upregulated miRNAs in malignancies, and regulates multiple pro-oncogenic pathways. We aimed to investigate the prognostic impact of miR-155 in resected stage III NSCLC patients.Tumor formalin-fixed, paraffin-embedded (FFPE) from 162 resected stage III NSCLC patients were collected. Total RNA including miRNA was extracted, and qRT-PCR was used to determine the expression of miR-155.Spearman rank correlation test showed a positive correlation between miR-155 expression and nodal status (r=0.169, P=0.032). MiR-155 expression had a significant prognostic impact in the total cohort (P0.001), in squamous cell carcinomas (P=0.002) and in adenocarcinomas (P=0.003). In N0-1 subgroup, miR-155 expression did not have a significant prognostic on overall survival in univariate analysis (P=0.319). In N2 subgroup, miR-155 had a negative prognostic effect on OS in univariate analysis (P0.001). Cox regression analysis revealed that miR-155 expression was unfavorable prognostic factors of OS (RR=2.311, 95%CI: 1.479-3.611, P0.001).High expression of miR-155 represents a valuable marker of poor clinical outcomes in patients with stage III NSCLC.背景与目的 pIII期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者5年生存率低于25%，需要寻找新的预后标志物，指导患者个体化治疗。MiR-155在许多肿瘤中表达上调，并对肿瘤有广泛的调控作用。本研究旨在探讨手术切除的pIII期NSCLC中miR-155的表达与预后的关系。方法 采用qRT-PCR法检测162例pIII期NSCLC手术患者福尔马林固定石蜡包埋组织（formalin-fixed, paraffin-embedded, FFPE）中miR-155的表达。结果 miR-155在pIII期NSCLC中表达与淋巴结转移程度正相关（r=0.169, P=0.032）。单因素生存分析显示在总体队列（P0.001）、鳞癌亚组（P=0.002）、腺癌亚组（P=0.003）中，miR-155高表达组的总体生存期（overall survival, OS）均低于miR-155低表达组。根据淋巴结转移程度分层分析显示在N0-1亚组中，miR-155高表达和低表达组间OS无统计学差异（P=0.319），在N2的患者中，miR-155高表达组OS显著低于miR-155低表达组（P0.001）。多因素生存分析显示miR-155高表达是影响患者预后的独立危险因素（RR=2.311, 95%CI: 1.479-3.611, P0.001）。结论 miR-15高表达不利于手术切除的pIII期NSCLC患者的总体生存，并且与淋巴结转移度正相关。MiR-155可作为评价pIII期NSCLC预后的生物标志物。

The predictive value of thymidine phosphorylase gene variants (TP, also called platelet-derived endothelial cell growth factor) and thrombocytosis were controversial and worthy of further study in gastrointestinal cancer (GIC) patients. We screened all of the common missense single nucleotide polymorphisms (MAF ≥ 0.1) in fluoropyrimidines (FU) pathway genes (including TP, TS, ENOSF1 and DPD). Three of them were selected and genotyped using Sequenom MassARRAY in 141 GIC patients. TP expression was assessed by immunohistochemistry. Our aim was to evaluate the prognostic significance of studied genes and platelet counts in GIC patients. Multivariate analyses indicated in rs11479-T allele carriers, platelet counts negatively correlated to overall survival. In addition, T allele of TP: rs11479 was associated with higher TP expression in cancer tissues. We suggest TP: rs11479 variant combined with platelet counts may be useful prognostic makers in GIC patients receiving first-line FU chemotherapy and thrombopoietin factor should be used with caution in the rs11479 T allele bearing patients.

Estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF-1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. LADE was induced with urethane in ovariectomized Kunming mice. Tumor-bearing mice were divided into seven groups: 17β-estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024 (IGF-1 inhibitor), E2+IGF-1, E2+IGF-1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ERα/ERβ, IGF-1, IGF-1R and Ki67 was examined using tissue-microarray-immunohistochemistry, and IGF-1, p-ERβ, p-IGF-1R, p-MAPK and p-AKT levels were determined based on Western blot analysis. Fluorescence-quantitative polymerase chain reaction was used to detect the mRNA expression of ERβ, ERβ2 and IGF-1R. Tumors were found in 93.88% (46/49) of urethane-treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF-1 group, tumor growth was significantly higher than in the E2 group (p0.05), the IGF-1 group (p0.05) and control group (p0.05). Similarly, the expression of ERβ, p-ERβ, ERβ2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT and Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p0.05). This study demonstrated for the first time that estrogen and IGF-1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ERβ1, ERβ2 and IGF-1R play important roles.