Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

Kodama, Tatsuhiko; Newberg, Justin Y.; Kodama, Michiko; Rangel, Roberto; Yoshihara, Kosuke; Tien, Jean C.; Parsons, Pamela H.; Wu, Hao; Finegold, Milton J.; Copeland, Neal G.; Jenkins, Nancy A.

doi:10.1073/pnas.1606876113

Cited by 57 publications

(47 citation statements)

References 67 publications

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“…Interestingly, aberrant activation of Met signaling was confirmed to be closely associated with tumor growth, angiogenesis, metastasis, and poor survival in HCC (36,37). Furthermore, Met can also activate an EMT program in human HCC cells (38). Consequently, miR-205/ SEMA4C probably promotes the metastasis and EMT of HCC by activating Met signaling.…”

Section: Discussionmentioning

confidence: 97%

MiR‐205 suppresses tumor growth, invasion, and epithelial‐mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma

Lin

et al. 2018

FASEB j.

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Growing evidence indicates that microRNAs are involved in tumorigenesis and progression of hepatocellular carcinoma (HCC). However, the functional mechanisms of miR-205 in HCC remain largely unknown. Here, we demonstrate that miR-205 expression was significantly down-regulated in HCC tissues and cell lines and was correlated with metastatic pathologic features and shorter disease-free and overall survival. Overexpression of miR-205 dramatically inhibited HCC cell proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor growth in vivo. We subsequently identified semaphorin 4C (SEMA4C) as a novel target of miR-205. Furthermore, high expression levels of SEMA4C were frequently found in HCC tissues and were associated with poor prognosis. Ectopic expression of SEMA4C restored the suppressive effect of overexpressed miR-205 on migration, invasion, and EMT. Taken together, our findings provide new insight into the critical role of miR-205 in regulating tumor growth, invasion, and EMT of HCC, suggesting miR-205 may serve as a promising therapeutic target and novel prognostic indicator for patients with HCC.-Lu, J., Lin, Y., Li, F., Ye, H., Zhou, R., Jin, Y., Li, B., Xiong, X., Cheng, N. MiR-205 suppresses tumor growth, invasion and epithelial-mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma.

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Section: Discussionmentioning

confidence: 97%

MiR‐205 suppresses tumor growth, invasion, and epithelial‐mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma

Lin

et al. 2018

FASEB j.

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“…The sleeping beauty (SB) transposon system has expanded the use of insertional mutagenesis for the study of many types of cancers (11)(12)(13)(14)(15)(16)(17)(18)(19)(20); and discovered candidate cancer genes (CCG) involved in the EMT and CSC pathways (21)(22)(23). To better understand the genes and pathways involved in the pathogenesis of TNBC, we performed an siRNA validation study of 40 SB-identified breast cancer TS genes identified in an SB mutagenesis screen performed in Pten mutant mice (24).…”

Section: Introductionmentioning

confidence: 99%

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

et al. 2017

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Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step sleeping beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG, whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A, and ZNF326 showed TS activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple epithelial-mesenchymal transition and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new TS genes in TNBC demonstrate the utility of two-step forward genetic screens in mice and offer an invaluable tool to identify novel candidate therapeutic pathways and targets.

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“…In our laboratory, we have performed transposon-based mutagenesis screens for a variety of cancer types and successfully identified many candidate cancer genes in a high-throughput manner (7,8). However, the lack of EOC mouse models that recapitulate human EOC has hampered our use of this technology for cancer gene discovery in EOC.…”

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confidence: 99%

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Kodama

Newberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further. Genetic and pharmacological inhibition showed that KPNB1 exerts its antitumor effects through multiphase cell cycle arrest and apoptosis induction. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle-related proteins, including p21, p27, and APC/ C. Clinically, EOC patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1. Interestingly, ivermectin, a Food and Drug Administration-approved antiparasitic drug, showed KPNB1-dependent antitumor effects on EOC, serving as an alternative therapeutic toward EOC patients through drug repositioning. Last, we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC both in vitro and in vivo than either drug alone. Our studies have thus identified a combinatorial therapy for EOC, in addition to a plethora of potential drug targets.ovarian cancer | KPNB1 | loss-of-function screen | CRISPR/Cas | RNAi

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Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

Cited by 57 publications

References 67 publications

MiR‐205 suppresses tumor growth, invasion, and epithelial‐mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma

MiR‐205 suppresses tumor growth, invasion, and epithelial‐mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

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