Anticancer Opportunity Created by Loss of Tumor Suppressor Genes.

Deletion of oncosuppressors occurs frequently in the cancer genome. A great deal of effort has been made to therapeutically restore the lost function of oncosuppressors, with little clinically translatable success, however. Reassuringly, besides the disappointing restoration endeavors, oncosuppressor loss can be therapeutically exploited in several other ways, such as the "synthetic lethality" strategies and the "therapeutic vulnerability" created by codeletion of neighboring genes. The study by Liu et al showed that codeletion of p53 and a neighboring essential gene POLR2A rendered colon cancer cells highly sensitive to further inhibition of POLR2A both in vitro and in vivo In recent years, several studies have reported similar phenomenon in a wide range of cancer types. In this focus article, we will introduce several kinds of anticancer opportunities created by the loss of oncosuppressors and discuss their mechanisms. Given the frequency of oncosuppressor loss in cancer, its therapeutic exploitation rather merits further investigation and may open a new window for oncotherapy.

LINE-1 in cancer: multifaceted functions and potential clinical implications.

Long interspersed nuclear element-1 (L1) retrotransposons are jumping genes that comprise 17% of human DNA. They utilize a ''copy-and-paste'' mechanism to propagate themselves throughout the genome via RNA intermediates, a process termed retrotransposition. L1s are active in the germ line and during embryogenesis, yet they are epigenetically suppressed in somatic cells. In cancer cells, however, L1s are aberrantly activated and may have a role in genome instability, one of the hallmarks of cancer pathogenesis. Their methylation states and retrotransposition activities are associated with and fluctuate during cancer initiation and progression, thus representing promising diagnostic biomarkers and therapeutic targets. During tumorigenesis, L1s exert both retrotransposition-dependent and retrotransposition-independent functions. The former may result in alterations in target gene expression or chromosomal rearrangement, or drive Alu and SVA, events that could function in tumorigenesis, whereas the latter can potentially exert epigenetic regulation by generating endo-siRNAs, forming chimeric L1 transcripts or changing the expression of adjacent genes by providing novel splicing sites or alternative promoters. Moreover, the L1 encoded proteins, ORF1p and ORF2p, may have pro-oncogenic potential by, for example, activating oncogenic transcriptional factors or sequestering oncosuppressors. Herein, we introduce the components and mechanisms of L1 retrotransposition, discuss the landscape, possible functions, and regulation of L1 activity in cancer, and seek their potential as diagnostic biomarkers and therapeutic targets.Genet Med 18 5, 431-439.

CRISPR-Cas9: a new and promising player in gene therapy.

First introduced into mammalian organisms in 2013, the RNA-guided genome editing tool CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) offers several advantages over conventional ones, such as simple-to-design, easy-to-use and multiplexing (capable of editing multiple genes simultaneously). Consequently, it has become a cost-effective and convenient tool for various genome editing purposes including gene therapy studies. In cell lines or animal models, CRISPR-Cas9 can be applied for therapeutic purposes in several ways. It can correct the causal mutations in monogenic disorders and thus rescue the disease phenotypes, which currently represents the most translatable field in CRISPR-Cas9-mediated gene therapy. CRISPR-Cas9 can also engineer pathogen genome such as HIV for therapeutic purposes, or induce protective or therapeutic mutations in host tissues. Moreover, CRISPR-Cas9 has shown potentials in cancer gene therapy such as deactivating oncogenic virus and inducing oncosuppressor expressions. Herein, we review the research on CRISPR-mediated gene therapy, discuss its advantages, limitations and possible solutions, and propose directions for future research, with an emphasis on the opportunities and challenges of CRISPR-Cas9 in cancer gene therapy.

Pseudogene in cancer: real functions and promising signature.

Pseudogenes were initially regarded as non-functional genomic fossils resulted from inactivating gene mutations during evolution. However, later studies revealed that they play a plethora of roles at multiple levels (DNA, RNA and/or protein) in diverse physiological and pathological processes, especially in cancer, both parental-gene-dependently and parental-gene-independently. Pseudogenes can interact with parental genes or other gene loci, leading to alteration in their sequences and/or transcriptional activities. Pseudogene-derived RNAs play multifaceted roles in post-transcriptional regulation as antisense RNAs, endogenous small-interference RNAs, competing endogenous RNAs and so on. Pseudogenic proteins can mirror, mimic or interfere with the functions of their parental counterparts. Herein, we discuss the general aspects (origination, classification, identification) of pseudogenes, focus on their multiple functions in cancer pathogenesis and prospect the potentials they hold as molecular signatures assisting in cancer reclassification and tailored therapy.

Violent head trauma in China: report of 2254 cases.

BACKGROUND: The occurrence of violent trauma has recently increased, and it has become both a social and medical problem in China. We are the first to explore violent head trauma in China. METHODS: Patients with violent head trauma were taken from all hospitalized patients with head trauma from January 2001 to December 2006 admitted to 11 hospitals in China. The rate, causes, age, sex, injury severity (GCS score), CT findings, management, outcome, and complications of patients with violent head trauma were retrospectively analyzed. RESULTS: Two thousand two hundred fifty-four (9.46%) patients with violent head trauma were found among a total of 23816 hospitalized patients with head trauma at 11 hospitals. Violent head trauma was caused by blunt objects (n = 1260, 55.90%), sharp/cutting instruments (n = 271, 12.02%), gunshots (n = 10, 0.44%), and others (n = 713, 31.63%). Violent head trauma was more likely to be found men (n = 1890, 83.85%) and in persons aged 21 to 40 years (n = 1216, 53.95%). In 2254 patients with violent head trauma, scalpel injury was seen in 1277 cases, skull fracture in 786 cases, cerebral contusion in 285 cases, and intracranial hematomas in 898 cases. Five hundred eighty-nine (26.13%) patients had body violent trauma besides violent head trauma. A GCS score of 13 to 15 was found in 1869 (82.92%) patients, 9 to 12 in 166 (7.36%), and 8 or less in 219 (9.72%). One thousand forty-two patients got surgical treatment, and another 1212 received medical management. One thousand nine hundred thirty-one (85.67%) patients had good recovery, 141 (6.47%) had moderate deficits, 36 (1.65%) had severe deficits, 7 (0.32%) had PVS, 63 (2.89%) died, and for the other 76, records were lost. CONCLUSIONS: Violent head trauma is certainly both a social and medical problem now, which indicates that violence should be controlled and that the human right of social safety needs to be improved in China.