Hang Su

The heavy fermion ferromagnet CeRh₆Ge₄ is the first example of a clean stoichiometric system where the ferromagnetic transition can be continuously suppressed by hydrostatic pressure to a quantum critical point. In order to reveal the outcome when the magnetic lattice of CeRh₆Ge₄ is diluted with non-magnetic atoms, this study reports comprehensive measurements of the physical properties of both single crystal and polycrystalline samples of La _x Ce_1–x Rh₆Ge₄. With increasing x, the Curie temperature decreases, and no transition is observed for x > 0.25, while the system evolves from exhibiting coherent Kondo lattice behaviors at low x to the Kondo impurity scenario at large x. Moreover, non-Fermi liquid behavior is observed over a wide doping range, which agrees well with the disordered Kondo model for 0.52 ≤ x ≤ 0.66, while strange metal behavior is revealed in the vicinity of x _c = 0.26.

E20637 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, which is the leading cancer killer in the world. Despite recent advance in diagnosis and therapy, the prognosis for NSCLC patients remains very poor, mainly due to the development of drug resistance and metastasis. The disruption of CCL2/CCR2 chemokine signaling has been shown to suppress cancer cell growth, migration and metastasis. CCL2 neutralizing antibodies, which have shown promising therapeutic efficacy in several cancer models, nevertheless, are not widely in use due to technical issues. CCR2 antagonism hence becomes an alternative way for cancer treatment. However, the efficacy of CCR2 antagonists on NSCLC progression remains poorly understood. Methods: The expression levels of CCL2 and CCR2 were examined using RT-PCR and Western Blotting among five NSCLC cell lines including A549, NCI-H460, RERF-LC-A1, LC99A and LC11-18. The effects of CCR2 antagonist, CAS 445479-97-0, on cell growth, migration and invasion were evaluated using WST-1 cell viability assay, transwell migration assay and Matrigel invasion assay respectively. A mouse metastatic model was deployed to compare the metastatic capacity of A549 cells between CAS 445479-97-0 treated and untreated groups. Results: We found A549 cell line had the highest levels of CCL2 secretion and CCR2 expression among all examined cell lines. CCL2 treatment promoted cell migration and invasion activity by 2.35-fold and 4.20-fold respectively in A549 cells, and this induction was significantly suppressed by CAS 445479-97-0 treatment. Interestingly, in cells with undetectable CCR2 expression, there is no difference in migration and invasion activity between experimental groups. Moreover, CCR2 antagonist completely reversed CCL2-induced A549 cell proliferation. Of great importance is that CCR2 antagonist suppressed the metastatic capacity by 35.42% in a mouse metastasis model. Conclusions: We demonstrated that CCR2 expression is a key factor in CCL2-mediated cell growth, migration and invasion, and that CAS 445479-97-0 effectively suppresses metastasis. Our data suggest that CCR2 antagonists are potential drugs for the treatment of CCR2-positive metastatic NSCLC patients.

Fibrillarin (FBL), an rRNA 2′-O-methyltransferase, has long been recognized as the enzymatic unit of the C/D box small nucleolar ribonucleoprotein (snoRNP) involved in the first step of pre-rRNA processing. It is not until recently that the link between FBL and cancers has been unveiled. As a direct regulatory target of Myc and p53, FBL is frequently upregulated in breast cancers and prostate cancers. High expression of FBL has also been shown to be associated with poor survival in patients with breast cancer. Our recent study found that FBL overexpression contributes to tumorigenesis and confers cellular resistance to chemodrugs. However, the underlying mechanism of chemoresistance elicited by FBL upregulation is still elusive. Here, we studied the molecular roles of FBL on p53 response. The p53 pathway in response to etoposide and actinomycin D were examined in a variety cell lines including U-2OS, MCF7, H1299, ZR75-1, A549 and an FBL inducible cell line. Western blotting and immunofluorescent staining were employed to examine protein level and their cellular localization. We found that ectopic expression of FBL enhanced the protein level of MDM2, resulting in decreased p53 accumulation and activity in response to chemodrugs. Interestingly, MDM2 was partially recruited to the nucleoli under stimuli. FBL depletion abrogated the nucleolar recruitment of MDM2 and subsequently dampened p53 activation. In conclusion, physiological level of FBL sequesters and stabilizes MDM2 in the nucleoli, therefore inhibits p53 degradation. When upregulated in cancers, FBL stabilizes nucleus MDM2 and promotes the degradation of p53 Citation Format: Teng Xu, Suthakar Ganapathy, Meijun Long, Chul Ha, Zhi-Min Yuan, Hang Su. Elevated level of Fibrillarin induces chemoresistance by interfering p53 pathway in cancers. []. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl): nr 5458. doi:10.1158/1538-7445.AM2015-5458

Reprogramming energy metabolism from oxidative phosphorylation to aerobic glycolysis, a common feature of human cancer, is associated with a relative acidic tumor microenvironment which can sometim...

Although aberrant microRNA (miRNA) expressions have been observed in different types of cancer, their pathophysiologic role and their relevance to tumorigenesis are still largely unknown. In this study, we first evaluated the expression of 308 miRNAs in human hepatocellular carcinoma (HCC) and normal hepatic tissues and identified 29 differentially expressed miRNAs in HCC tissues. miR-101, a significantly down-regulated miRNA, was further studied in greater detail because the signal pathway(s) regulated by miR-101 and the role of miR-101 in tumorigenesis have not yet been elucidated. Interestingly, decreased expression of miR-101 was found in all six hepatoma cell lines examined and in as high as 94.1% of HCC tissues, compared with their nontumor counterparts. Furthermore, ectopic expression of miR-101 dramatically suppressed the ability of hepatoma cells to form colonies in vitro and to develop tumors in nude mice. We also found that miR-101 could sensitize hepatoma cell lines to both serum starvation– and chemotherapeutic drug–induced apoptosis. Further investigation revealed that miR-101 significantly repressed the expression of luciferase carrying the 3′-untranslated region of Mcl-1 and reduced the endogenous protein level of Mcl-1, whereas the miR-101 inhibitor obviously up-regulated Mcl-1 expression and inhibited cell apoptosis. Moreover, silencing of Mcl-1 phenocopied the effect of miR-101 and forced expression of Mcl-1 could reverse the proapoptotic effect of miR-101. These results indicate that miR-101 may exert its proapoptotic function via targeting Mcl-1. Taken together, our data suggest an important role of miR-101 in the molecular etiology of cancer and implicate the potential application of miR-101 in cancer therapy. [Cancer Res 2009;69(3):1135–42]

A G > C polymorphism (rs2910164) is located in the stem region opposite to the mature miR-146a sequence, which results in a change from G:U pair to C:U mismatch in the stem structure of miR-146a precursor. Here, we elucidated the biological significance of this polymorphism, based on cancer association study and cell model system. The cancer association study included 479 hepatocellular carcinoma (HCC) and 504 control subjects. We found that the genotype distribution of this polymorphism in HCC cases was significantly different from that in control subjects (P = 0.026). The association between the genotype and the risk of HCC was further analyzed using multivariate unconditional logistic regression, with adjustment for sex, age and hepatitis B virus status. The results revealed that male individuals with GG genotype were 2-fold more susceptible to HCC (odds ratio = 2.016, 95% confidence interval = 1.056–3.848, P = 0.034) compared with those with CC genotype. We next examined the influence of this polymorphism on the production of mature miR-146a and found that G-allelic miR-146a precursor displayed increased production of mature miR-146a compared with C-allelic one. Further investigations disclosed that miR-146a could obviously promote cell proliferation and colony formation in NIH/3T3, an immortalized but non-transformed cell line. These data suggest that the G > C polymorphism in miR-146a precursor may result in important phenotypic traits that have biomedical implications. Our findings warrant further investigations on the relation between microRNA polymorphism and human diseases.

This study was purposed to investigate the angiogenin (ANG) expression in COS-7 cells and its biological activity. The gene of angiogenin was obtained from mononuclear cells of peripheral blood by using RT-PCR and inserted into eukaryotic expression vector of pcDNA3.1. After being transfected into COS-7 cells, the recombinant ANG was identified by Western blot assay. The function of promoting proliferation of ANG to ECV304 cells was detected by MTT method, and its activity of vascularization was analyzed by chick embryo chorioallantois treated by the culture supernatant after transfection with pcDNA3.1-ang. The result showed that recombinant ANG was expressed in COS-7 cells after transfection for 24 to 36 hours. It could specifically react with monoclonal antibody against ANG. The recombinant ANG could obviously promote the proliferation of ECV304 cells. In contrast with the control group, the culture supernatant of pcDNA3.1-ang transfected group could stimulate the angiogenesis in embryo chorioallantois. It is concluded that the ang transiently expresses in COS-7 cells, and its expression product obviously stimulates the cell proliferation and angiogenesis.