Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells

Zhang, Zhiping; Jiang, Guanchao; Yang, Fan; Wang, Jun

doi:10.4161/cbt.5.11.3297

Cited by 55 publications

(45 citation statements)

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“…This mutation is a key initiator, as evidenced by its presence in PanIN lesions (Kanda et al 2012;Murphy et al 2013) and the production of PanIN lesions in oncogenic Kras-driven GEMMs (Hezel et al 2006;Perez-Mancera et al 2012a). While some PDAC cell lines in two-dimensional (2D) culture can tolerate shRNA-mediated KRAS extinction (Singh et al 2009), most PDAC cells remain highly addicted to oncogenic KRAS for tumor maintenance in three-dimensional (3D) culture (Zhang et al 2006;Fujita-Sato et al 2015) and inducible oncogenic Kras GEMMs with advanced tumors (Collins et al 2012;Ying et al 2012). These data strongly support the view that KRAS is a prime therapeutic target for PDAC.…”

Section: The Kras Oncogene Signaling Networkmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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Section: The Kras Oncogene Signaling Networkmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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“…RNA interference (RNAi) [1][2][3] was first discovered in Caenorhabditis elegans as a potent gene-silencing mechanism. 4 The inhibition of specific gene expression by means of RNAi has also been achieved in mammalian cells by directly introducing short dsRNA (siRNA) into cells, which avoids a response evoked by long dsRNA.…”

Section: Introductionmentioning

confidence: 99%

Allele-specific cancer cell killing in vitro and in vivo targeting a single-nucleotide polymorphism in POLR2A

et al. 2009

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Cancer is one of the diseases for which RNA interference is a potential therapeutic approach. Genes involved in the promotion or maintenance of tumor growth are obvious targets for RNAi. RNAi is also considered an attractive additional approach to conventional chemotherapy for cancer treatment. Moreover, siRNAs have shown a high specificity for their molecular target mRNAs as they can selectively inhibit cancer-promoting genes that differ by a point mutation. Loss of heterozygosity (LOH) reduces genes to hemizygosity in cancer cells and presents an absolute difference between normal and cancer cells. The regions of LOH are usually much larger than the tumor suppressor gene, which is lost, and has been shown to contain genes that are essential for cell survival. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man. SNPs in essential genes that are frequently affected by LOH can be used as a target for a therapy against cancer cells with LOH. We have designed siRNAs against the gene of the large subunit of RNA polymerase II (POLR2A), a gene located in close proximity to the tumor suppressor gene p53, which frequently shows LOH in cancer cells. It is shown in vitro that siRNA can selectively inhibit POLR2A expression dependent on its genotype. Furthermore, cancer cell proliferation and tumor growth inhibition in nude mice was genotype dependent. We conclude that siRNA can be used for genotype-specific inhibition of tumor growth targeting an SNP in POLR2A in vivo.

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“…90% of pancreatic cancers, 50% of colon cancers, 30% of lung cancers) supports the idea that aberrant Ras activation is a driving force in the development and advancement of these malignancies [10]. The use of in vitro knockdown studies [45] and transgenic mouse models [46], [47] further confirmed this idea that mutant Ras is highly transforming.…”

Section: Ras Activation In Breast Cancersupporting

confidence: 53%

The Ras effector NORE1A forms a tumor suppressor complex with BRCA1.

Nelson

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Ras proteins function as molecular signaling switches that can stimulate multiple mitogenic pathways in response to extracellular signaling. Oncogenic activation of Ras by structural mutation is a highly transforming event in ~1/3 of human cancers. However, aberrant Ras activation can also promote oncogene-induced senescence. This Rasinduced irreversible growth arrest is a physiological process that acts as a barrier to malignancy. The mechanisms by which Ras drives senescence and how this process is bypassed during Ras-driven transformation remains poorly understood.Although mutations in the RAS gene are extremely rare in human breast cancer, the Ras signaling pathway is constitutively activated in roughly half of all primary breast tumors. This is largely due to aberrant activation of upstream regulators of Ras, like the EGFR family member Her2 and inactivation of negative Ras regulators, such as NF1.NORE1A (RASSF5) is a direct Ras effector that acts as a tumor suppressor by promoting apoptosis and senescence. Expression of NORE1A is frequently lost in primary breast tumors and breast cancer cell lines, though its mechanism of action in breast cancer pathogenesis remains unclear. vi BRCA1 is a tumor suppressor that plays a key role in DNA DSB repair. Loss of BRCA1 is associated with hereditary breast and ovarian cancer, and is also thought to play a role in sporadic breast cancer. Recently, BRCA1 was shown to play a role in both Her2 and Ras senescence, but the mechanism underlying the communication between Her2/Ras and BRCA1 was not identified.I have discovered that NORE1A forms an endogenous, Her2/Ras-regulated complex with BRCA1. I show that dual suppression of NORE1A and BRCA1 has a synergistic effect on transformation. Furthermore, I show that NORE1A loss suppresses the BRCA1-mediated senescence effect. Finally, I show that NORE1A and BRCA1 synergize to modulate DNA repair. Thus, I identify a novel tumor suppressor complex that connects Her2/Ras senescence signaling to BRCA1 in breast cancer. GAPs stabilize the catalytic machinery of Ras, enhancing its intrinsic ability to hydrolyze GTP into GDP and returning Ras to its inactive conformation.5 In addition to mitogenic signaling, activated Ras can also drive apoptosis and senescence.Ras signaling through Raf can promote p53-mediated apoptosis, and has also been implicated in senescence induction via p21 and p16. Ras-mediated activation of RASSF1A leads to apoptosis via activation of pro-apoptotic BAX proteins, or by activation of the pro-apoptotic Hippo pathway via phosphorylation of the MST kinases.RASSF1A has also been reported to drive senescence via p53-independent regulation of p21. Ras-mediated activation of NORE1A can promote p53-dependent upregulation of p21 to drive cell cycle arrest or senescence.12 Ras growth inhibitory effectorsThe RASSF familyThere are ten RASSF family members (along with various isoforms), which are now split into two groups: the "classical" members (RASSF1-6), which contain an RA domain and a SARAH domain at their C-term...

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Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells

Cited by 55 publications

References 0 publications

Genetics and biology of pancreatic ductal adenocarcinoma

Genetics and biology of pancreatic ductal adenocarcinoma

Allele-specific cancer cell killing in vitro and in vivo targeting a single-nucleotide polymorphism in POLR2A

The Ras effector NORE1A forms a tumor suppressor complex with BRCA1.

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