Enhanced target gene knockdown by a bifunctional shRNA: a novel approach of RNA interference.

Abstract:

:RNA interference (RNAi) is a natural cellular regulatory process that inhibits gene expression by transcriptional, post-transcriptional and translational mechanisms. Synthetic approaches that emulate this process (small interfering RNA (siRNA), short hairpin RNA (shRNA)) have been shown to be similarly effective in this regard. We developed a novel 'bifunctional' RNAi strategy, which further optimizes target gene knockdown outcome. A bifunctional construct (bi-sh-STMN1) was generated against Stathmin1, a critical tubulin modulator that is overexpressed in human cancers. The bifunctional construct is postulated to concurrently repress the translation of the target mRNA (cleavage-independent, mRNA sequestration and degradation) and degrade (through RNase H-like cleavage) post-transcriptional mRNA through cleavage-dependent activities. Bi-sh-STMN1 showed enhanced potency and durability in parallel comparisons with conventional shRNA and siRNAs targeting the same sequence. Enhanced STMN1 protein knockdown by bi-sh-STMN1 was accompanied by target site cleavage at the mRNA level showed by the rapid amplification of complementary DNA ends (RACE) assay. Bi-sh-STMN1 also showed knockdown kinetics at the mRNA level consistent with its multieffector silencing mechanisms. The bifunctional shRNA is a highly effective and advantageous approach mediating RNAi at concentrations significantly lower than conventional shRNA or siRNA. These results support further evaluations.

journal_name

Cancer Gene Ther

journal_title

Cancer gene therapy

authors

Rao DD,Maples PB,Senzer N,Kumar P,Wang Z,Pappen BO,Yu Y,Haddock C,Jay C,Phadke AP,Chen S,Kuhn J,Dylewski D,Scott S,Monsma D,Webb C,Tong A,Shanahan D,Nemunaitis J

doi

10.1038/cgt.2010.35

subject

Has Abstract

pub_date

2010-11-01 00:00:00

pages

780-91

issue

11

eissn

0929-1903

issn

1476-5500

pii

cgt201035

journal_volume

17

pub_type

杂志文章
  • Therapeutic anti-glioma effect of the combined action of PCSK inhibitor with the anti-tumoral factors secreted by Poly (I:C)-stimulated macrophages.

    abstract::Macrophages plasticity is a key feature in cancer progression. Neoplastic cells can alter their immune functions and orient them into a pro-tumoral phenotype. In this context, we developed a new therapeutic strategy to switch macrophages phenotype and reactivate their anti-tumoral functions. We showed a dual activity ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-020-00286-1

    authors: Rose M,Duhamel M,Aboulouard S,Kobeissy F,Tierny D,Fournier I,Rodet F,Salzet M

    更新日期:2021-01-05 00:00:00

  • Screening siRNAs targeting a novel gene (HA117) and the development of a derivative recombinant adenovirus delivery system.

    abstract::A novel gene, HA117, was discovered in our previous work. Using the pSOS-HUS vector method which we designed at previous study, we screened for small interfering RNAs (siRNAs) that targeted HA117. The pSOS-HUS siRNA screening results were verified and a delivery system was developed that contained a recombinant adenov...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2011.32

    authors: Zheng GH,Luo Q,Jin XQ,Guo YX,Xu YH

    更新日期:2011-09-01 00:00:00

  • Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand.

    abstract::The tumor-suppressive role of Farnesoid X receptor (FXR) in colorectal tumorigenesis supports restoring FXR expression as a novel therapeutic strategy. However, the complicated signaling network and tumor heterogeneity hinder the effectiveness of FXR agonists in the clinical setting. These difficulties highlight the i...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-020-00239-8

    authors: Yu J,Yang K,Zheng J,Zhao W,Sun X

    更新日期:2020-10-13 00:00:00

  • E1A, E1B double-restricted replicative adenovirus at low dose greatly augments tumor-specific suicide gene therapy for gallbladder cancer.

    abstract::Combination therapy with replicative oncolytic viruses is a recent topic in innovative cancer therapy, but few studies have examined the efficacy of oncolytic adenovirus plus replication-deficient adenovirus carrying a suicide gene. We aim to evaluate whether an E1A, E1B double-restricted oncolytic adenovirus, AxdAdB-...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2008.67

    authors: Fukuda K,Abei M,Ugai H,Kawashima R,Seo E,Wakayama M,Murata T,Endo S,Hamada H,Hyodo I,Yokoyama KK

    更新日期:2009-02-01 00:00:00

  • Modulation of miRNA activity in human cancer: a new paradigm for cancer gene therapy?

    abstract::MicroRNAs (miRNAs) were discovered more than a decade ago as noncoding, single-stranded small RNAs (approximately 22 nucleotides) that control the timed gene expression pattern in Caenorhabditis elegans life cycle. A number of these evolutionarily conserved, endogenous miRNAs have been shown to regulate mammalian cell...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/cgt.2008.8

    authors: Tong AW,Nemunaitis J

    更新日期:2008-06-01 00:00:00

  • Simultaneous inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNFalpha-mediated apoptosis.

    abstract::Lung cancer is the most frequently occurring cancer in the world and causes more deaths in the United States than does colon, breast, and prostate cancer combined. Despite advances in treatment modalities including radiation, surgery, and chemotherapy, the overall survival in lung cancer remains low. The cytokine tumo...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700394

    authors: Sanlioglu S,Luleci G,Thomas KW

    更新日期:2001-11-01 00:00:00

  • Use of targeted cationic liposomes in enhanced DNA delivery to cancer cells.

    abstract::Cationic liposomes are considered to be safe vectors for gene transfer, but they are less efficient at delivering DNA to cells when compared with retroviral vectors. Cationic liposomes complexed with DNA were targeted to specific cells in vitro by means of monoclonal antibodies (mAbs) or ligands associated with the li...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:

    authors: Kao GY,Change LJ,Allen TM

    更新日期:1996-07-01 00:00:00

  • A "combination oligonucleotide" antisense strategy to downregulate thymidylate synthase and decrease tumor cell growth and drug resistance.

    abstract::Thymidylate synthase (TS) catalyzes de novo production of thymidylate for DNA synthesis and cell proliferation. As such, TS has been a target of antitumor chemotherapy for many years. Our laboratory has identified several antisense oligodeoxynucleotides (ODNs) that downregulate TS mRNA and protein, inhibit cell prolif...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700566

    authors: Berg RW,Ferguson PJ,Vincent MD,Koropatnick DJ

    更新日期:2003-04-01 00:00:00

  • Immunotherapy for murine K1735 melanoma: combinatorial use of recombinant adenovirus expressing CD40L and other immunomodulators.

    abstract::We have constructed and tested five recombinant adenoviruses (Ads) that express a variety of immunomodulators, including CD40 ligand (CD40L), a potent costimulator of several components of the immune system. We demonstrate that CD40L expressed from Ad in K1735 mouse melanoma cells leads to a strong reduction in tumori...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700475

    authors: Peter I,Nawrath M,Kamarashev J,Odermatt B,Mezzacasa A,Hemmi S

    更新日期:2002-07-01 00:00:00

  • Inhibition of Gli2 suppresses tumorigenicity in glioblastoma stem cells derived from a de novo murine brain cancer model.

    abstract::The prognosis of glioblastoma remains poor despite intensive research efforts. Glioblastoma stem cells (GSCs) contribute to tumorigenesis, invasive capacity, and therapy resistance. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a stem cell marker, is involved in the maintenance of GSCs, although ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-020-00282-5

    authors: Tanigawa S,Fujita M,Moyama C,Ando S,Ii H,Kojima Y,Fujishita T,Aoki M,Takeuchi H,Yamanaka T,Takahashi Y,Hashimoto N,Nakata S

    更新日期:2021-01-07 00:00:00

  • Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors.

    abstract::In this study, we investigated the safety and efficacy in cancer patients of a single intra-tumor injection of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene (AdV/TK) followed by systemic administration of ganciclovir (GCV). In 18 patients with malignant tumors refractory to standard...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2009.19

    authors: Xu F,Li S,Li XL,Guo Y,Zou BY,Xu R,Liao H,Zhao HY,Zhang Y,Guan ZZ,Zhang L

    更新日期:2009-09-01 00:00:00

  • Antiproliferative activity of a triplex-forming oligonucleotide recognizing a Ki-ras polypurine/polypyrimidine motif correlates with protein binding.

    abstract::The Ki-ras gene is frequently mutated and/or overexpressed in human cancer. Since it is suspected to play a key role in the pathogenesis of many tumors, there is interest to search for strategies aiming at the specific inhibition of this oncogene. In this paper, we investigated the capacity of a 20 mer G-rich oligonuc...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700722

    authors: Cogoi S,Ballico M,Bonora GM,Xodo LE

    更新日期:2004-07-01 00:00:00

  • Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy in BT4C rat glioma model.

    abstract::Adenovirus (Adv)-mediated herpes simplex virus thymidine kinase (adv/tk) gene therapy combined with ganciclovir (GCV) medication is a promising approach for the treatment of malignant glioma. However, optimal administration and the effect of possible adjuvant treatments have not been fully examined. In the present stu...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700515

    authors: Tyynelä K,Sandmair AM,Turunen M,Vanninen R,Vainio P,Kauppinen R,Johansson R,Vapalahti M,Ylä-Herttuala S

    更新日期:2002-11-01 00:00:00

  • Transfection of NF-κB decoy oligodeoxynucleotide suppresses pulmonary metastasis by murine osteosarcoma.

    abstract::Nuclear factor-kappa B (NF-κB) has a pivotal role in the progression and distant metastasis of cancers, including malignant bone tumors. To inhibit NF-κB activation, a new molecular therapy using synthetic double-stranded oligodeoxynucleotide (ODN) as a 'decoy' cis element against NF-κB has been developed. To determin...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2010.75

    authors: Nishimura A,Akeda K,Matsubara T,Kusuzaki K,Matsumine A,Masuda K,Gemba T,Uchida A,Sudo A

    更新日期:2011-04-01 00:00:00

  • Improved gene transfer selectivity to hepatocarcinoma cells by retrovirus vector displaying single-chain variable fragment antibody against c-Met.

    abstract::Engineered retroviruses are widely used vectors for cancer gene therapy approaches. However, the ability to target cells of therapeutic interest while controlling the expression of the transferred genes would improve both the efficiency and the safety of viral vectors. In this study, we investigated the ability of a r...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700640

    authors: Nguyen TH,Loux N,Dagher I,Vons C,Carey K,Briand P,Hadchouel M,Franco D,Jouanneau J,Schwall R,Weber A

    更新日期:2003-11-01 00:00:00

  • Immunosuppression promotes reovirus therapy of colorectal liver metastases.

    abstract::Mortality due to colorectal cancer (CRC) is high and is associated with the development of liver metastases. Approximately 40% of human CRCs harbor an activating mutation in the KRAS oncogene. Tumor cells with activated KRAS are particularly sensitive to Reovirus T3D, a non-pathogenic oncolytic virus. The efficacy of ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700949

    authors: Smakman N,van der Bilt JD,van den Wollenberg DJ,Hoeben RC,Borel Rinkes IH,Kranenburg O

    更新日期:2006-08-01 00:00:00

  • Adenovirus-mediated IKKbetaKA expression sensitizes prostate carcinoma cells to TRAIL-induced apoptosis.

    abstract::Despite the fact that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells, TRAIL resistance in cancer cells has challenged the use of TRAIL as a therapeutic agent. First, prostate carcinoma cell lines (DU145, LNCaP and PC3) were screened for sensitivity to a...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700877

    authors: Sanlioglu AD,Koksal IT,Karacay B,Baykara M,Luleci G,Sanlioglu S

    更新日期:2006-01-01 00:00:00

  • TMB: a promising immune-response biomarker, and potential spearhead in advancing targeted therapy trials.

    abstract::Immune checkpoint inhibition (ICI) has revolutionized cancer treatment, and produced durable responses in many cancer types. However, there remains a subset of patients that do not respond despite their tumors exhibiting PD-L1 expression, which highlights the need for additional biomarkers relevant to response. Here, ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/s41417-020-0174-y

    authors: Choucair K,Morand S,Stanbery L,Edelman G,Dworkin L,Nemunaitis J

    更新日期:2020-12-01 00:00:00

  • Combined suicide and granulocyte-macrophage colony-stimulating factor gene therapy induces complete tumor regression and generates antitumor immunity.

    abstract::The use of prodrug-activated ("suicide") gene therapy has been shown to be effective in inducing tumor regression when only a small proportion of tumor cells contains the suicide gene. These experiments were designed to test whether additional therapeutic benefit may be obtained by stimulating the immune response. Mur...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700259

    authors: Jones RK,Pope IM,Kinsella AR,Watson AJ,Christmas SE

    更新日期:2000-12-01 00:00:00

  • Virotherapy clinical trials for regional disease: in situ immune modulation using recombinant poxvirus vectors.

    abstract::The ability of viruses to readily infect tumor cells both in vitro and in vivo has resulted in their study as antitumor agents through a variety of strategies. Replicating and conditionally replicating viruses and recombinant viruses encoding genes for toxins and/or prodrugs have been studied for their direct antitumo...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/sj.cgt.7700538

    authors: Mastrangelo MJ,Lattime EC

    更新日期:2002-12-01 00:00:00

  • Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein.

    abstract::We have described three potential adenovirus type 5 (Ad5)-based replication-competent cancer gene therapy vectors named KD1, KD3, and VRX-007. All three vectors overexpress an Ad5 protein named Adenovirus Death Protein (ADP, also named E3-11.6 K protein). ADP is required for efficient lysis of Ad5-infected cells and s...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700555

    authors: Toth K,Tarakanova V,Doronin K,Ward P,Kuppuswamy M,Locke JE,Dawson JE,Kim HJ,Wold WS

    更新日期:2003-03-01 00:00:00

  • Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer cell-dependent and -independent antitumor effects.

    abstract::We examined whether novel cytokines, interleukin (IL)-21 and IL-23, that were expressed in tumors could produce antitumor effects in the inoculated mice. Human pancreatic cancer AsPC-1 cells were retrovirally transduced with murine IL-21 or IL-23 (p19-linked p40) gene (AsPC-1/IL-21, AsPC-1/IL-23) and were injected int...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700630

    authors: Ugai S,Shimozato O,Yu L,Wang YQ,Kawamura K,Yamamoto H,Yamaguchi T,Saisho H,Sakiyama S,Tagawa M

    更新日期:2003-10-01 00:00:00

  • MicroRNA let-7b suppresses human gastric cancer malignancy by targeting ING1.

    abstract::MicroRNAs (miRNAs) are important regulators that play key roles in tumorigenesis and tumor progression. In this study, we investigate whether let-7b acts as a tumor suppressor to inhibit invasion and metastasis in gastric cancers. We analyzed the expression of let-7b in 60 pair-matched gastric neoplastic and adjacent ...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2014.75

    authors: Han X,Chen Y,Yao N,Liu H,Wang Z

    更新日期:2015-04-01 00:00:00

  • Manufacture of T cells using the Sleeping Beauty system to enforce expression of a CD19-specific chimeric antigen receptor.

    abstract::T cells can be reprogrammed to redirect specificity to tumor-associated antigens (TAAs) through the enforced expression of chimeric antigen receptors (CARs). The prototypical CAR is a single-chain molecule that docks with TAA expressed on the cell surface and, in contrast to the T-cell receptor complex, recognizes tar...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/cgt.2014.69

    authors: Singh H,Moyes JS,Huls MH,Cooper LJ

    更新日期:2015-03-01 00:00:00

  • Chimeric antigen receptors for treatment of glioblastoma: a practical review of challenges and ways to overcome them.

    abstract::Glioblastoma (GBM) is by far the most common and the most aggressive of all the primary brain malignancies. No curative therapy exists, and median life expectancy hovers at around 1 year after diagnosis, with a minute fraction surviving beyond 5 years. The difficulty in treating GBM lies in the cancer's protected nich...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章,评审

    doi:10.1038/cgt.2016.46

    authors: Sengupta S,Mao G,Gokaslan ZS,Sampath P

    更新日期:2017-03-01 00:00:00

  • Calcium-sensing receptor antagonist NPS-2143 suppresses proliferation and invasion of gastric cancer cells.

    abstract::NPS-2143 is a calcium-sensing receptor (CaSR) antagonist that has been demonstrated to possess anticancer activity. To date, the effects of NPS-2143 on gastric cancer (GC) cell growth, motility, and apoptosis have not been investigated. In the present study, we firstly investigated the expression of CaSR in GC tissues...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-019-0128-4

    authors: Zhang ZL,Li ZR,Li JS,Wang SR

    更新日期:2020-08-01 00:00:00

  • Her-2 expression regulated by downregulation of miR-9 and which affects chemotherapeutic effect in breast cancer.

    abstract::This study aimed to identify microRNAs (miRs), the deregulated expression of which leads to the activation of oncogenic pathways in human breast cancer (BC). miRs are classes of endogenous, small, noncoding RNAs that regulate gene expression aberrantly in human tumor tissues. A total of 39 out of 123 tumoral and match...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2014.82

    authors: Sun G,Sun L,Liu Y,Xing H,Wang K

    更新日期:2017-05-01 00:00:00

  • Silencing of long non-coding RNA XIST represses gastric cancer progression through blocking NFκB pathway via inhibiting HNF4A-mediated transcription of EPHA1.

    abstract::Gastric cancer (GC) is a common cancer and a leading cause of cancer-related deaths worldwide. Recent studies have supported the important role of long non-coding RNAs (lncRNAs) in GC progression. This study identified functional significance of X inactive specific transcript (XIST) in GC. The expression of XIST and E...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/s41417-020-00220-5

    authors: Li P,Wang L,Li P,Hu F,Cao Y,Tang D,Ye G,Li H,Wang D

    更新日期:2020-11-16 00:00:00

  • The effects of radiation on antitumor efficacy of an oncolytic adenovirus vector in the Syrian hamster model.

    abstract::We report that radiation enhances the antitumor efficacy of the oncolytic adenovirus vector VRX-007 in Syrian hamster tumors. We used tumor-specific irradiation of subcutaneous tumors and compared treatment options of radiation alone or combined with VRX-007 and cyclophosphamide (CP). Radiation therapy further augment...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/cgt.2013.50

    authors: Young BA,Spencer JF,Ying B,Toth K,Wold WS

    更新日期:2013-09-01 00:00:00

  • Inhibition of hepatocarcinoma by systemic delivery of Apoptin gene via the hepatic asialoglycoprotein receptor.

    abstract::Specificity is a prerequisite for systemic gene therapy of hepatocarcinoma. In vitro, the tumor-specific viral death effector Apoptin selectively induces apoptosis in malignant hepatic cells. Intratumoral treatment of xenografted subcutaneous hepatomas with Apoptin results in tumor regression. Here, we report a system...

    journal_title:Cancer gene therapy

    pub_type: 杂志文章

    doi:10.1038/sj.cgt.7700985

    authors: Peng DJ,Sun J,Wang YZ,Tian J,Zhang YH,Noteborn MH,Qu S

    更新日期:2007-01-01 00:00:00