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// Fangfang Tao 1, * , Xinxin Tian 2, 3, * and Zhiqian Zhang 3, 4 1 Department of Immunology and Microbiology, Basic Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, People's Republic of China 2 Department of Biochemistry and Biophysics, Texas A and M University and Texas AgriLife Research, College Station, TX 77843-2128, USA 3 Tianjin International Joint Academy of Biomedicine (TJAB), Tianjin 300457, People's Republic of China 4 State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, People's Republic of China * These authors contributed equally to this work Correspondence to: Zhiqian Zhang, email: zhangzhiqian@tjab.org Keywords: prostate cancer; LncRNAs; PCAT3; PCAT9; miR-203-SNAI2 axis Received: September 26, 2017 Accepted: December 05, 2017 Published: January 12, 2018 ABSTRACT Long non-coding RNAs (lncRNAs) have been reported to be of great importance in the formation and progression of a wide range of human carcinomas including prostate cancer (PCa). Among them, PCAT3 and PCAT9 have been identified as two prostate tissue-specific lncRNAs and are up-regulated in PCa. However, their roles in the biological characteristics of PCa have not been fully elucidated. In the present study, our data revealed that knockdown of PCAT3 and PCAT9 suppressed cellular proliferation, invasion, migration, angiogenesis and stemness in androgen-dependent LNCaP and 22Rv1 cells. Strikingly, bioinformatics analysis predicted that both PCAT3 and PCAT9 transcripts had two conserved binding sties for miR-203. Meanwhile, dual luciferase report assays revealed that miR-203 could suppress the luciferase activities of reporter plasmids carrying the binding site of miR-203 on the mRNA of PCAT3 or PCAT9. Quantitative RT-PCR (qRT-PCR) and RNA fluorescence in situ hybridization (RNA-FISH) showed that miR-203 mimic reduced the expression of PCAT3 and PCAT9 both in LNCaP and 22Rv1 cells. We also noted that both PCAT3 and PCAT9 inhibited miR-203 expression and alleviated repression on the expression of SNAI2, a critical regulator of epithelial-mesenchymal transition directly targeted by miR-203. Functionally, silence of miR-203 or ectopic expression of SNAI2 attenuated the inhibitory effect of PCAT3 and PCAT9 knockdown on cell proliferation and migration in vitro , and xenograft growth in vivo . Taken together, our data suggested that the PCAT3/PCAT9-miR-203-SNAI2 axis may serve as a promising diagnostic and therapeutic target for PCa.

Glioblastoma (GBM) is a deadly and incurable brain tumor. Although microRNAs (miRNAs) play critical roles in regulating the cancer cell phenotype, the underlying mechanisms of how they regulate tumorigenesis are incompletely understood. We previously showed that miR-203a is expressed at relatively low levels in GBM patients, and ectopic miR-203a expression in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by interferon (IFN) or temozolomide in vitro, and inhibited GBM tumorigenesis in vivo. Here we show that ectopic expression of miR-203a in GBM cell lines promotes the IFN response pathway as evidenced by increased IFN production and IFN-stimulated gene (ISG) expression, and high basal tyrosine phosphorylation of multiple STAT proteins. Importantly, we identified that miR-203a directly suppressed the protein levels of ataxia-telangiectasia mutated (ATM) kinase that negatively regulates IFN production. We found that high ATM expression in GBM correlates with poor patient survival and that ATM expression is inversely correlated with miR-203a expression. Knockout of ATM expression and inhibition of ATM function in GBM cell lines inhibited cell proliferation and migration, increased sensitivity to apoptosis induced by therapeutic agents in vitro, and markedly suppressed GBM tumor growth and promoted animal survival. In contrast, restoring ATM levels in GBM cells ectopically expressing miR-203a increased tumorigenicity and decreased animal survival. Our study suggests that low miR-203a expression in GBM suppresses the interferon response through an ATM-dependent pathway.

// Qing Xu 1 , Mei Liu 1 , Ju Zhang 2 , Liyan Xue 3 , Guo Zhang 1 , Chenfei Hu 1 , Zaozao Wang 1 , Shun He 1 , Lechuang Chen 1 , Kai Ma 1 , Xianghe Liu 1 , Yahui Zhao 1 , Ning Lv 3 , Shufang Liang 4 , Hongxia Zhu 1 , Ningzhi Xu 1, 4 1 Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 2 Division of Proteomics, Beijing Institute of Genomics, Chinese Academy of Science, Beijing, China 3 Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 4 State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, P. R. China Correspondence to: Hongxia Zhu, email: drhxzhu@cicams.ac.cn Ningzhi Xu, email: xuningzhi@cicams.ac.cn Keywords: KLF4, p21, survivin, miR-203, senescence Received: November 20, 2015 Accepted: July 26, 2016 Published: August 11, 2016 ABSTRACT Kruppel-like factor 4 (KLF4) is a transcription factor and functions as a tumor suppressor or tumor promoter in different cancer types. KLF4 regulates many gene expression, thus affects the process of cell proliferation, differentiation, and apoptosis. Recently, KLF4 was reported to induce senescence during the generation of induced pluripotent stem (iPS) cells, but the exact mechanism is still unclear. In this study, we constructed two doxycycline-inducing KLF4 cell models, and demonstrated overexpression of KLF4 could promote cell senescence, detected by senescence-associated β-galactosidase activity assay. Then we confirmed that p21, a key effector of senescence, was directly induced by KLF4. KLF4 could also inhibit survivin, which could indirectly induce p21. By miRNA microarray, we found a series of miRNAs regulated by KLF4 and involved in senescence. We demonstrated that KLF4 could upregulate miR-203, and miR-203 contributed to senescence through miR-203-survivin-p21 pathway. Our results suggest that KLF4 could promote cell senescence through a complex network: miR-203, survivin, and p21, which were all regulated by overexpression of KLF4 and contributed to cell senescence.

// Qingping Jiang 1, * , Ying Zhou 2, 3, * , Huiling Yang 2, 5, * , Libo Li 3, * , Xiaojie Deng 2 , Chao Cheng 2 , Yingying Xie 3 , Xiaojun Luo 3 , Weiyi Fang 2, 3 , Zhen Liu 2, 4 1 Department of Pathology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China 2 Cancer Research Institute, Southern Medical University, Guangzhou 510515, China 3 Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China 4 Department of Pathology, Medical University of Guangzhou, Guangzhou 510182, China 5 Sino-American Cancer Research Institute, Guangdong Medical College, Dongguan 523808, China * These authors have contributed equally to this work Correspondence to: Weiyi Fang, email: fangweiyi1975@163.com Zhen Liu, email: narcissus_jane@163.com Keywords: miR-203a, ZEB2, NPC, tumor stemness, chemotherapy resistance Received: March 06, 2016 Accepted: July 18, 2016 Published: August 30, 2016 ABSTRACT miR-203 is a tumor suppressor that is disregulated in numerous malignancies including nasopharyngeal carcinoma (NPC). However, the role of miR-203 in suppressing tumor stemness, chemotherapy resistance as well as its molecular mechanisms are unclear. In this study, we observed that miR-203 suppressed cell migration, invasion, tumor stemness, and chemotherapy resistance to cisplatin (DDP) in vitro and in vivo . miR-203 exerted these effects by targeting ZEB2 and downstream epithelial-mesenchymal transition (EMT) and tumor stemness signals. Interestingly we observed that miR-203 expression was directly suppressed by ZEB2 via targeting its promoter, which significantly reduced cell migration, invasion, tumor stemness, and chemotherapy resistance in NPC cells. Finally, we found that miR-203 was negatively correlated with ZEB2 expression in NPC tissues and tumor spheres. Our data demonstrate a directly negative feedback loop between miR-203 and ZEB2 participating in tumor stemness and chemotherapy resistance, highlighting the therapeutic potential of targeting this signal for NPC chemotherapy.

// Soon Won Choi 1, 2, * , Ji-Hee Shin 1, 2, * , Jae-Jun Kim 1, 2 , Tae-Hoon Shin 1, 2 , Yoojin Seo 1, 2 , Hyung-Sik Kim 1, 3, 4 , Kyung-Sun Kang 1, 2 1 Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea 2 Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea 3 Pusan National University School of Medicine, Busan 49241, Republic of Korea 4 Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea * These authors contributed equally to this work Correspondence to: Kyung-Sun Kang, email: kangpub@snu.ac.kr Keywords: miR-203, photoreceptor, neural retina, AESC, UCB-MSC Received: January 07, 2016 Accepted: May 12, 2016 Published: June 07, 2016 ABSTRACT Stem cell-based photoreceptor differentiation strategies have been the recent focus of therapies for retinal degenerative diseases. Previous studies utilized embryonic stem (ES) cells and neural retina differentiation cocktails, including DKK1 and Noggin. Here, we show a novel microRNA-mediated strategy of retina differentiation from somatic stem cells, which are potential allogeneic cell sources. Human amniotic epithelial stem cells (AESCs) and umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) treated with a retina differentiation cocktail induced gene expressions of retina development-relevant genes. Furthermore, microRNA-203 (miR-203) is abundantly expressed in human AESCs and human UCB-MSCs. This miR-203 is predicted to target multiple retina development-relevant genes, particularly DKK1, CRX, RORβ, NEUROD1, NRL and THRB. The inhibition of miR-203 induced a retina differentiation of AESCs and UCB-MSCs. Moreover, successive treatments of anti-miR-203 led to the expression of both mature photoreceptor (PR) markers, rhodopsin and opsin. In addition, we determined that CRX, NRL and DKK1 are direct targets of miR-203 using a luciferase assay. Thus, the work presented here suggests that somatic stem cells can potentially differentiate into neural retina cell types when treated with anti-miR-203. They may prove to be a source of both PR subtypes for future allogeneic stem cell-based therapies of non-regenerative retina diseases.

// Hongzhan Liao 1,* , Yifeng Bai 2,* , Shengcong Qiu 1 , Lei Zheng 3 , Lianyan Huang 4 , Tianzhu Liu 1 , Xin Wang 1 , Yanting Liu 1 , Ningbo Xu 1 , Xiaohui Yan 5 and Hongbo Guo 1 1 Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Repair and Regeneration of Guangdong, Zhujiang Hospital, Southern Medical University, Guangzhou, China 2 Department of Oncology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China 3 Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China 4 School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China 5 Research Center of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Hongbo Guo, email: // Keywords : chemotherapy resistance, epithelial-mesenchymal transition, microRNAs, glioblastoma, SNAI2 Received : January 16, 2015 Accepted : February 10, 2015 Published : March 12, 2015 Abstract Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration, invasion, and drug resistance in several types of cancer. In this study, our aim was to clarify microRNAs (miRNAs)-related mechanisms underlying EMT followed by acquired resistance to chemotherapy in glioblastoma (GBM). We used multiple methods to achieve our goal including microarray analysis, qRT-PCR, western blotting analysis, loss/gain-of-function analysis, luciferase assays, drug sensitivity assays, wound-healing assay and invasion assay. We found that miR-203 expression was significantly lower in imatinib-resistant GBM cells (U251AR, U87AR) that underwent EMT than in their parental cells (U251, U87). Ectopic expression of miR-203 with miRNA mimics effectively reversed EMT in U251AR and U87AR cells, and sensitized them to chemotherapy, whereas inhibition of miR-203 in the sensitive lines with antisense oligonucleotides induced EMT and conferred chemoresistance. SNAI2 was identified as a direct target gene of miR-203. The knockdown of SNAI2 by short hairpin RNA (shRNA) inhibited EMT and drug resistance. In GBM patients, miR-203 expression was inversely related to SNAI2 expression, and those tumors with low expression of miR-203 experienced poorer clinical outcomes. Our findings indicate that re-expression of miR-203 or targeting SNAI2 might serve as potential therapeutic approaches to overcome chemotherapy resistance in GBM.

// Xiang Zhou 1 , Dimple Natino 2 , Zili Qin 3 , Dong Wang 1 , Zhen Tian 4 , Xuan Cai 1 , Bo Wang 5 and Xijing He 1 1 Department of Orthopaedics, Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China 2 Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA 3 Department of Otolaryngology, Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China 4 Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, China 5 Department of Pharmacology, School of Basic Medical Science, Xi’an Jiaotong University Health Science Center, Xi'an, China Correspondence to: Xijing He, email: xijing_h@vip.tom.com Keywords: osteosarcoma; circRNA-0008717; miR-203; Bmi-1 Received: September 11, 2017 Accepted: November 16, 2017 Published: January 02, 2018 ABSTRACT Circular RNA (circRNA) is a key regulator in the development and progression of human cancers, however its role in osteosarcoma tumorigenesis is not well understood. The present study aims to investigate the expression profiles and potential modulation of circRNA on osteosarcoma carcinogenesis. Human circRNA microarray was performed to screen for abnormally expressed circRNA in osteosarcoma tissue and circRNA-0008717 was identified as one circRNA significantly upregulated in osteosarcoma tissue. Osteosarcoma patients with high circRNA-0008717 expression had shortened survival. Gain and loss functional assays suggested that knockdown of circRNA-0008717 suppressed cell proliferation, migration and invasion, but promoted cell apoptosis. By using biotin-labeled circRNA-0008717 probe to perform RNA precipitation in osteosarcoma cells, we identified miR-203 as the circ0008717-associated microRNA. Subsequently, Bmi-1 was identified as the functional target of miR-203. In addition, overexpression of circRNA-0008717 in osteosarcoma could elevate Bmi-1 expression, resulting in the promotion of osteosarcoma cell proliferation and invasion. Furthermore, the tumor promoting effect of circRNA-0008717 was abolished by miR-203 mimics or Bmi-1 silencing vector. In conclusion, circRNA-0008717 plays an oncogenic role in osteosarcoma and may serve as a promising prognostic biomarker for osteosarcoma patients. Therefore, silence of circRNA-0008717 could be a future direction to develop a novel treatment strategy.

// Yuki Takano 1, 2, * , Takaaki Masuda 1, * , Hisae Iinuma 3 , Rui Yamaguchi 4 , Kuniaki Sato 1 , Taro Tobo 5 , Hidenari Hirata 1 , Yosuke Kuroda 1 , Sho Nambara 1 , Naoki Hayashi 1 , Tomohiro Iguchi 1 , Shuhei Ito 1 , Hidetoshi Eguchi 1 , Takahiro Ochiya 6 , Katsuhiko Yanaga 2 , Satoru Miyano 4 and Koshi Mimori 1 1 Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan 2 Department of Surgery, Jikei University School of Medicine, Tokyo, Japan 3 Department of Surgery, Teikyo University, Tokyo, Japan 4 Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan 5 Department of Pathology, Kyushu University Beppu Hospital, Beppu, Japan 6 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Koshi Mimori, email: kmimori@beppu.kyushu-u.ac.jp Keywords: miR-203, exosome, tumor-host interaction, tumor-associated macrophage, colorectal cancer Received: March 06, 2017 Accepted: June 26, 2017 Published: August 07, 2017 ABSTRACT A primary tumor can create a premetastatic niche in distant organs to facilitate the development of metastasis. The mechanism by which tumor cells communicate with host cells to develop premetastatic niches is unclear. We focused on the role of microRNA (miR) signaling in promoting metastasis. Here, we identified miR-203 as a signaling molecule between tumors and monocytes in metastatic colorectal cancer (CRC) patients. Notably, high expression of serum exosomal miR-203 , a major form in circulation, was associated with distant metastasis and an independent poor prognostic factor, whereas low expression in tumor tissues was a poor prognostic factor in CRC patients. We also found that exosomes carrying miR-203 from CRC cells were incorporated into monocytes and miR-203 could promote the expression of M2 markers in vitro , suggesting miR-203 promoted the differentiation of monocytes to M2-tumor-associated macrophages (TAMs). In a xenograft mouse model, miR-203 -transfected CRC cells developed more liver metastasis compared to control cells. In conclusion, serum exosomal miR-203 expression is a novel biomarker for predicting metastasis, possibly via promoting the differentiation of monocytes to M2-TAMs in CRC. Furthermore, we propose the concept of site-dependent functions for miR-203 in tumor progression.

Several microRNAs (miRNA) have been implicated in H. pylori related gastric cancer (GC). However, the molecular mechanism of miRNAs in GC has not been fully understood. In this study, we reported that miR-203 is significantly down-regulated in H. pylori positive tissues and cells and in tumor tissues with important functional consequences. Ectopic expression of miR-203 dramatically suppressed cell proliferation and invasion. We found that miR-203 strongly reduced the expression of CASK oncogene in GC cells. Similar to the restoring miR-203 expression, CASK down-regulation inhibited cell growth and invasion, whereas CASK over-expression rescued the suppressive effect of miR-203. These results can also be found in nude mice. In clinical specimens, CASK was over-expressed in tumors and H. pylori positive tissues and its mRNA levels were inversely correlated with miR-203 expression. Taken together, our results indicated that miR-203 functions as a growth-suppressive miRNA in H. pylori related GC, and that its suppressive effects are mediated mainly by repressing CASK expression.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with limited therapeutic options. Temozolomide (TMZ) is a novel cytotoxic agent used as first-line chemotherapy for GBM, however, some individual cells can't be isolated for surgical resection and show treatment-resistance, thus inducing poor prognosis. By using the HiSeq sequencing and bioinformatics methods, we identified lncRNAs showing different expression levels in TMZ-resistant and non-resistant patients. RT-qPCR was then performed in tissues and serum samples, and lncRNA MALAT1 was finally identified to show considerable discriminating potential to identify responding patients from non-responding patients. Moreover, high serum MALAT1 expression was associated with poor chemoresponse and survival in GBM patients receiving TMZ treatment. Subsequently, the TMZ resistant cell lines were established, and the CCK8 assay showed that lncRNA MALAT1 knockdown significantly reversed TMZ resistance in GBM cells. The gain and loss-function experiments revealed that miR-203 was down-regulated by MALAT1 and this interaction has reciprocal effects. Besides, thymidylate synthase (TS) mRNA was identified as a direct target of miR-203. LncRNA MALAT1 inhibition re-sensitized TMZ resistant cells through up-regulating miR-203 and down-regulating TS expression. On the other hand, MALAT1 overexpression promoted resistance by suppressing miR-203 and promoting TS expression. In conclusion, our integrated approach demonstrates that enhanced expression of lncRNA MALAT1 confers a potent poor therapeutic efficacy and inhibition of MALAT1 levels could be a future direction to develop a novel therapeutic strategy to overcome TMZ resistance in GBM patients.

// Pin-Dong Li 1, 2, * , Jian-Li Hu 1, * , Charlie Ma 2 , Hong Ma 1 , Jing Yao 1 , Li-Li Chen 2 , Jing Chen 1 , Tian-Tian Cheng 3 , Kun-Yu Yang 1 , Gang Wu 1 , Wen-Jie Zhang 4 and Ru-Bo Cao 1 1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China 2 Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA 3 Cancer Center of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510059, China 4 Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, China * These authors have contributed equally to this work Correspondence to: Ru-Bo Cao, email: caorubao@126.com Keywords: long non-coding RNA, PVT1, LASP1, miR-203, esophageal squamous cell carcinoma Received: November 01, 2016 Accepted: January 16, 2017 Published: March 03, 2017 ABSTRACT Long non-coding RNAs are a group of non-coding RNAs longer than 200 nucleotides and possess diverse functions and exhibit exquisite cell-specific and developmental dynamic expression patterns. The role of the long non-coding RNA PVT1 in esophageal squamous cell carcinoma remains unsolved. Here, we showed that PVT1 expression is significantly up-regulated in ESCC tumor samples compared with their normal counterparts. Knockdown of PVT1 suppressed tumor growth in vitro and in vivo . Further studies revealed that silence of PVT1 lead to up-regulation of miR-203, and vice versa. Moreover, LASP1 was found to be downregulated after knockdown of PVT1 and overexpression of LASP1 attenuated the tumor-suppressive roles of PVT1 knockdown. Our results suggest that PVT1 promote ESCC progression via functioning as a molecular sponge for miR-203 and LASP1 and provide the first evidence of dysregulated PVT1/miR-203/LASP1 axis in ESCC.

// T. Peter Kingham 2, * , Hoang C.B. Nguyen 1, * , Jian Zheng 2 , Ioannis T. Konstantinidis 2 , Eran Sadot 2 , Jinru Shia 3 , Deborah Kuk 4 , Steven Zhang 1 , Leonard Saltz 5 , Michael I. D’Angelica 2 , William R. Jarnagin 2 , Hani Goodarzi 6, 7, 8 , Sohail F. Tavazoie 1, 5 1 Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA 2 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 6 Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA 7 Department of Urology, University of California, San Francisco, San Francisco, CA, USA 8 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA * These authors contributed equally to this work Correspondence to: T. Peter Kingham, email: kinghamt@mskcc.org Hani Goodarzi, email: hani.goodarzi@ucsf.edu Sohail F. Tavazoie, email: stavazoie@mail.rockefeller.edu Keywords: microRNA, miR-203, colorectal liver metastasis, survival, resection Received: July 25, 2016 Accepted: November 14, 2016 Published: December 07, 2016 ABSTRACT Background: Resection of colorectal liver metastasis (CRLM) can be curative. Predicting which patients may benefit from resection, however, remains challenging. Some microRNAs (miRNAs) become deregulated in cancers and contribute to cancer progression. We hypothesized that miRNA expression can serve as a prognostic marker of survival after CRLM resection. Results: MiR-203 was significantly overexpressed in tumors of short-term survivors compared to long-term survivors. R1/R2 margin status and high clinical risk score (CRS) were also significantly associated with short-term survival (both p = 0.001). After adjusting for these variables, higher miR-203 expression remained an independent predictor of shorter survival ( p = 0.010). In the serum cohort, high CRS and KRAS mutation were significantly associated with short-term survival ( p = 0.005 and p = 0.026, respectively). After adjusting for CRS and KRAS status, short-term survivors were found to have significantly higher miR-203 levels ( p = 0.016 and p = 0.033, respectively). Materials and Methods: We employed next-generation sequencing of small-RNAs to profile miRNAs in solid tumors obtained from 38 patients who underwent hepatectomy for CRLM. To validate, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed on 91 tumor samples and 46 preoperative serum samples. Conclusions: After CRLM resection, short-term survivors exhibited significantly higher miR-203 levels relative to long-term survivors. MiR-203 may serve as a prognostic biomarker and its prognostic capacity warrants further investigation.

// Man Kit Siu 1,2,* , Wassim Abou-Kheir 3,* , Juan Juan Yin 4,* , Yung-Sheng Chang 1 , Ben Barrett 4 , Florent Suau 4 , Orla Casey 4 , Wei-Yu Chen 5 , Lei Fang 4 , Paul Hynes 4 , Yao-Yu Hsieh 1,6 ,Yen-Nien Liu 1,7 , Jiaoti Huang 8 and Kathleen Kelly 4 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 2 Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 3 Department of Anatomy, Cell Biology and Physiological Sciences Faculty of Medicine, American University of Beirut, Beirut, Lebanon 4 Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 5 Department of Pathology, Wan Fang Hospital, College of Medicine, Taipei Medical University, Taipei, Taiwan 6 Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 7 Center of Excellence for Cancer Research, Wan Fang Hospital, College of Medicine, Taipei Medical University, Taipei, Taiwan 8 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA * These authors contributed equally to this work. Correspondence: Yen-Nien Liu, email: // Keywords : Bone metastasis/Epidermal growth factor receptor (EGFR)/Prostate cancer/miR-203 /KRAS/Tyrosine kinase inhibitors (TKIs) resistance Received : February 20, 2014 Accepted : May 18, 2014 Published : May 20, 2014 Abstract Activation of EGFR signaling pathway leads to prostate cancer bone metastasis; however, therapies targeting EGFR have demonstrated limited effectiveness and led to drug resistance. miR-203 levels are down-regulated in clinical samples of primary prostate cancer and further reduced in metastatic prostate cancer. Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands ( EREG and TGFA ) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.

// Amelie Hailer 1,* , Thomas GP Grunewald 2,* , Martin Orth 1 , Cora Reiss 1 , Burkhard Kneitz 3 , Martin Spahn 3 and Elke Butt 1 1 Institute for Clinical Biochemistry and Pathobiochemistry, University Clinic of Wuerzburg, Grombuehlstrasse 12, 97080 Wuerzburg, Germany 2 INSERM Unit 830, Genetics and Biology of Cancers, Institute Curie Research Center, 26 rue d’Ulm, 75248 Paris, France 3 Urology and Pediatric Urology, University Clinic of Wuerzburg, Oberduerrbacher Strasse 6, 97080 Wuerzburg, Germany * These authors contributed equally to this work Correspondence: Elke Butt, email: // Keywords : LASP1, prostate cancer, mir-203, PSA, LNCaP Received : March 18, 2014 Accepted : April 25, 2014 Published : April 27, 2014 Abstract Several studies have linked overexpression of the LIM and SH3 domain protein 1 (LASP1) to progression of breast, colon, liver, and bladder cancer. However, its expression pattern and role in human prostate cancer (PCa) remained largely undefined. Analysis of published microarray data revealed a significant overexpression of LASP1 in PCa metastases compared to parental primary tumors and normal prostate epithelial cells. Subsequent gene-set enrichment analysis comparing LASP1-high and -low PCa identified an association of LASP1 with genes involved in locomotory behavior and chemokine signaling. These bioinformatic predictions were confirmed in vitro as the inducible short hairpin RNA-mediated LASP1 knockdown impaired migration and proliferation in LNCaP prostate cancer cells. By immunohistochemical staining and semi-quantitative image analysis of whole tissue sections we found an enhanced expression of LASP1 in primary PCa and lymph node metastases over benign prostatic hyperplasia. Strong cytosolic and nuclear LASP1 immunoreactivity correlated with PSA progression. Conversely, qRT-PCR analyses for mir-203, which is a known translational suppressor of LASP1 in matched RNA samples revealed an inverse correlation of LASP1 protein and mir-203 expression. Collectively, our results suggest that loss of mir-203 expression and thus uncontrolled LASP1 overexpression might drive progression of PCa.