Testicular germ cell tumors (TGCT) originate from germ cells. The 129-Ter and M19 (129.MOLF-Chr19 consomic) mouse strains have extremely high incidences of TGCTs. We found that the expression levels of Sf1-encoded splicing factor 1 (SF1) can modulate the incidence of TGCTs. We generated mice with inactivated Sf1. Sf1 null mice (Sf1−/−) died before birth. Mice with one intact allele of Sf1 (Sf1+/−) were viable but expressed reduced levels of Sf1. When Sf1-deficient mice (Sf1+/−) were crossed to the 129-Ter and M19 strains, we observed decreased incidence of TGCTs in Sf1+/−;Ter and Sf1+/−;M19/+ mice compared with that in control cohorts. Therefore, Sf1 deficiency protects against TGCT development in both strains. Sf1 is expressed in the testes. We found that Sf1 levels vary significantly in the testes of inbred strains such as 129 and MOLF, and as such Sf1 is an oncogenic tumor-susceptibility factor from 129. Our results also highlight the complications involved in evaluating Sf1 levels and TGCT incidences. When a large number of tumor-promoting factors are present in a strain, the protective effect of lower Sf1 levels is masked. However, when the dosage of tumorpromoting factors is reduced, the protective effect of lower Sf1 levels becomes apparent. SF1 is involved in splicing of specific pre-mRNAs in cells. Alternate splicing generates the complex proteosome in eukaryotic cells. Our data indicate that Sf1 levels in mouse strains correlate with their incidences of TGCTs and implicate the importance of splicing mechanisms in germ cell tumorigenesis. Cancer Res; 70(18); 7264-72. ©2010 AACR.

The RNA binding protein DEAD-END (DND1) is one of the few proteins known to regulate microRNA (miRNA) activity at the level of miRNA-mRNA interaction. DND1 blocks miRNA interaction with the 3′-untranslated region (3′-UTR) of specific mRNAs and restores protein expression. Previously, we showed that the DNA cytosine deaminase, APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide like 3), interacts with DND1. APOBEC3 has been primarily studied for its role in restricting and inactivating retroviruses and retroelements. In this report, we examine the significance of DND1-APOBEC3 interaction. We found that while human DND1 inhibits miRNA-mediated inhibition of P27, human APOBEC3G is able to counteract this repression and restore miRNA activity. APOBEC3G, by itself, does not affect the 3′-UTR of P27. We found that APOBEC3G also blocks DND1 function to restore miR-372 and miR-206 inhibition through the 3′-UTRs of LATS2 and CX43, respectively. In corollary experiments, we tested whether DND1 affects the viral restriction function or mutator activity of APOBEC3. We found that DND1 does not affect APOBEC3 inhibition of infectivity of exogenous retrovirus HIV (ΔVif) or retrotransposition of MusD. In addition, examination of Ter/Ter;Apobec3−/− mice, lead us to conclude that DND1 does not regulate the mutator activity of APOBEC3 in germ cells. In summary, our results show that APOBEC3 is able to modulate DND1 function to regulate miRNA mediated translational regulation in cells but DND1 does not affect known APOBEC3 function.

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BackgroundEarly detection of lung cancer using low-dose computed tomography (LDCT) can potentially reduce morbidity and mortality. However, LDCT for lung cancer screening, especially in low income countries, has been underutilized. The objective of this study was to evaluate the prevalence and the potential personal, social, and economic barriers of lung cancer screening using LDCT.MethodsA total sample of 156 smokers and 200 general physicians was collected during December 2016-February 2017 from community settings in Karachi, Pakistan. Two separate questionnaires were constructed to characterize participants’ knowledge, attitudes, and practices regarding lung cancer screening. Screening-eligible smokers and physicians were asked to identify patient barriers to screening and were asked their opinion regarding most effective approach for increasing awareness of screening guidelines.ResultsThe majority of smokers' (n=91, 58.3%) and physicians' (n=131, 65.7%) beliefs about the US Preventive Services Task Force (USPSTF) eligibility criteria were inconsistent with the actual recommendations. Major barriers to screening included financial cost, lack of patient counseling and health anxiety related to screening. Over two-thirds (n=105, 67.3%) of smokers were receptive to further information about LDCT screening, and half (n=78, 50.0%) favored one-on-one counseling by their physician, compared to other media. Only one-third (n=65, 33.3%) of physicians reported use of LDCT screening, although 54.5% (n=108) felt that screening implementation would be very effective in their practice.ConclusionLDCT screening is currently an uncommon practice in Pakistan. Financial cost, inadequate doctor-patient communication, and lack of awareness of guidelines among both patients and physicians are the major barriers in the utilization of LDCT screening.