Ribozyme targeting HPV16 E6E7 transcripts in cervical cancer cells suppresses cell growth and sensitizes cells to chemotherapy and radiotherapy

Zheng, Yuhua; Zhang, Jiren; Rao, Zhiguo

doi:10.4161/cbt.3.11.1215

Cited by 30 publications

(18 citation statements)

References 12 publications

(13 reference statements)

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“…Moreover, HH ribozymes that can specifically target HPV-16 E6/E7 transcripts inhibited cell growth promoting apoptosis and also inhibited tumor growth in nude mice [89,90].…”

Section: The Hammerhead (Hh) Ribozymementioning

confidence: 99%

Molecular Approaches to Cervical Cancer Therapy

Álvarez-Salas

DiPaolo²

2007

CDDT

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Cervical cancer is the second most common malignancy in women worldwide. Two HPV strains, HPV-16 and 18, occur in the 70% of untreated cancers. Expression of viral oncogenes E6 and E7 disrupt the cell cycle by interfering with p53 and p107(Rb). It is known that HPV infection is necessary but insufficient to cause malignancy. Furthermore, persistence of HPV-16 or 18 in women does not necessarily result in cancer. Persistence indicates the importance of other factors for malignant conversion of high-grade HPV infection. The multi-step cervical carcinogenesis process is amendable to molecular therapeutics such as therapeutic nucleic acids (TNAs). TNA-based therapies for cervical carcinoma include ribozymes, antisense oligonucleotides (AS-ODNs) and small interfering RNAs (siRNAs). In vitro experiments with TNAs successfully inhibited E6/E7 expression and caused induction of apoptosis and/or senescence in cervical carcinoma cells. Early ribozyme and AS-ODN approaches showed promise as therapeutic moieties for cervical cancer. Despite the very high in vitro efficiency of siRNA-based therapies they present the same issues that burdened clinical development of ribozymes and AS-ODNs. These issues include intracellular target accessibility, specificity and delivery. Ribozymes are useful for functional genomic studies including diagnosis. Moreover, AS-ODNs appear better suited for clinical protocols because recent advances in nucleic acid chemistry allow higher cell uptake with very low off-target effects leading to actual AS-ODNs clinical applications. By using combined treatments with multiple targets it will be possible to apply TNAs directly to the cancerous cervix to destroy viral RNA and obliterate the tumor.

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“…Moreover, HH ribozymes that can specifically target HPV-16 E6/E7 transcripts inhibited cell growth promoting apoptosis and also inhibited tumor growth in nude mice [89,90].…”

Section: The Hammerhead (Hh) Ribozymementioning

confidence: 99%

Molecular Approaches to Cervical Cancer Therapy

Álvarez-Salas

DiPaolo²

2007

CDDT

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“…1 The mechanisms underlying the carcinogenesis of high risk HPVs have been studied extensively, showing that the E6 and E7 proteins are the oncoproteins, which interact respectively with essential components of the cellular regulatory machinery, leading to the dysregulated proliferation and transformation of the infected-cells. [2][3][4] Many important functions also have been attributed to the high risk HPV-E6 protein, including targeting and degradation of p53. [5][6][7] In contrast, the physiological roles of the low risk HPV-E6 protein remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Two different HPV-11E6 fusion proteins trap p53 in the cytoplasm and induce apoptosis

Sun

Zhang²,

Lei³

et al. 2008

Cancer Biology & Therapy

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Mucosal high risk human papillomaviruses (HPVs) have been shown to be the major cause of cervical cancer. However, the reason why the low risk HPVs only cause proliferative but non-invasive lesions of infected epithelia remains elusive. Because p53 interacts with high risk HPVs E6 and plays a very important role in carcinogenesis, it is assumed that low risk HPVs E6 might interact with p53 in a different pattern. We used mammalian green fluorescent protein (GFP) tagged and polyhistidine (His) tagged proteins expression systems to express HPV-11E6 fusion proteins in wild-type (wt) p53 cell lines, such as 293T and MCF-7 cells to trace the traffic and location of E6s and p53. We showed that: (1) Following transfection, HPV-11E6 was predominantly expressed in the cytoplasm; (2) Using immunocytochemistry and Western blotting, endogenous wt p53 was shown to be trapped in cytoplasm by HPV-11E6 expression. (3) Apoptosis was increased in HPV-11E6 expressed cells. In conclusion, the entrapment of endogenous wt p53 in cytoplasm by the low risk HPV-11E6 may be one of the reasons why low risk HPV is not able to induce malignant transformation.

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“…Targeted therapy against cervical cancer such as anti-EGFR, anti-angiogenesis and mTOR inhibition has been proposed and shRNA inhibition of E6 and E7 could be combined with these targeted therapies to increase efficacy. Zheng et al showed that ribozyme inhibited E6 and E7, resulted in increased sensitivity to chemotherapeutic agents and radiotherapy [47] . SiRNA against E6/E7 has also been shown to have a synergistic effect with cisplatin in causing apoptosis [48] .…”

Section: Discussionmentioning

confidence: 99%

Intra-tumor injection of lentiviral-vector delivered shRNA targeting human papillomavirus E6 and E7 oncogenes reduces tumor growth in a xenograft cervical cancer model in mice

Chen¹,

McMillan

2012

JST

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Objectives: HPV is known to play a key role in the growth and maintenance of cervical cancer. Its early genes E6 and E7 can activate several intracellular signal pathways for carcinogenesis. Studies have shown that in vitro knockdown of E6 and E7 can reduce the survival ability of cervical cancer cell lines. In this study, we tested the effect of a lentiviral shRNA against E6/E7 on the tumor growth of xenografted cervical cancer HeLa cells. Methods:In vitro, the growth of HeLa cells transduced with lentiviral shRNA against E6/E7 was compared to controls. In vivo, the RAG -/-mice, which are deficient in T and B lymphocytes were used to establish the HeLa xenografted model. In the treatment group, shRNA against E6/E7 was injected into the tumor directly 30 days after HeLa cell injection when tumors have formed and the injection was repeated at day 60. A lentiviral vector without shRNA was injected in the control group.Results: HeLa cells transduced with lentiviral shRNA against E6/E7 grew slower than those with transduced with the control vector. The difference in growth rate was significant at day 4. We also observed that lentiviral shRNA significantly reduced the size of xenografted tumors compared with controls. The average tumor weight is 60% of the controls. Conclusions:Our results provide evidence that RNAi may be used for the treatment of cervical cancer by intra-tumor injection.

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Ribozyme targeting HPV16 E6E7 transcripts in cervical cancer cells suppresses cell growth and sensitizes cells to chemotherapy and radiotherapy

Cited by 30 publications

References 12 publications

Molecular Approaches to Cervical Cancer Therapy

Molecular Approaches to Cervical Cancer Therapy

Two different HPV-11E6 fusion proteins trap p53 in the cytoplasm and induce apoptosis

Intra-tumor injection of lentiviral-vector delivered shRNA targeting human papillomavirus E6 and E7 oncogenes reduces tumor growth in a xenograft cervical cancer model in mice

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