RESUMO
PC4 is a chromatin-associated protein and transcriptional coactivator whose role in gene regulation by wild-type p53 is now well known. Little is known about the roles of PC4 in tumor cells bearing mutant p53 genes. We show that PC4 associates with one of the tumor-associated gain-of-function p53 mutants, R273H. This association drives its recruitment to two promoters, UBE2C and MDR1, known to be responsible for imparting aggressive growth and resistance to many drugs. Here, we introduced a peptide that disrupts the PC4-R273Hp53 interaction to tumor cells bearing the R273HTP53 gene, which led to a lowering of MDR1 expression and abrogation of drug resistance in a mutant-specific manner. The results suggest that the PC4-R273Hp53 interaction may be a promising target for reducing proliferation and drug resistance in tumors.
RESUMO
Ovarian cancer has sustained as a major cause of cancer-related female mortality owing to its aggressive nature and a dearth of early detection markers. Ets1 oncoprotein, a transcription factor belonging to the Ets family, is a well-established promoter of epithelial to mesenchymal transition (EMT) and a prospective malignancy marker in ovarian cancer. Our study establishes Ets1 as a regulator of mitochondrial fission-fusion dynamics through Drp1 augmentation via direct binding at DNM1L (DRP1) promoter. Ets1 overexpression-mediated Drp1 increment resulted in mitochondrial load reduction and compromised OXPHOS Complex 5 (ATP synthase) expression, facilitating a greater reliance on glycolysis over OXPHOS. Furthermore, our work demonstrates that inhibition of mitochondrial fission through molecular or pharmacological inhibition of Drp1 successfully mitigates Ets1-associated EMT in both in vitro and in vivo syngeneic mice model. Collectively, our data highlight the role of Drp1-mediated mitochondrial fragmentation in driving Ets1-mediated bioenergetic alterations and EMT/invasion in ovarian cancer.
RESUMO
INTRODUCTION: Human papillomavirus (HPV) types 16/18 are reportedly most common in cervical cancer (CaCx) with geographical variation of genotypes. HPV16 predominates both in squamous cell carcinoma (SCC) and adenocarcinoma in India, contrary to reported global predominance of HPV18 in the latter. Our study was aimed to determine the occurrence of HPV16/18 among histopathological types of cervical intra-epithelial neoplasia (CIN) and invasive CaCx from North Bengal, India and to identify any major deviation from the known Indian scenario of distribution of HPV16/18 genotypes in cases of SCC and adenocarcinoma. MATERIALS AND METHODS: This was a retrospective, cross-sectional, case-only type of study, in which 40 cases were histopathologically diagnosed as CIN/CaCx, on which polymerase chain reaction (PCR), deoxyribonucleic acid (DNA)-sequencing and bioinformatics by basic search local alignment tool were performed for HPV-genotyping. STATISTICAL ANALYSIS: The distribution of HPV genotypes among cases of SCC and adenocarcinoma was compared by Fisher's exact-test. RESULTS: HPV was detected in 97.5% (39/40) cases. HPV16-infected cases (32/39; 82.05%) predominated over HPV18-infected ones (7/39; 17.95%). However, HPV18-only infection was significantly (P = 0.0045, one-sided Fisher's exact test) more among adenocarcinoma (3/4; 75%) than SCC (2/26; 7.69%) contrary to HPV16-only infection (SCC = 24/26, 92.31%; adenocarcinoma = 1/4; 25%) whereas both CIN3 cases were HPV16-positive. CONCLUSION: Predominance of HPV18 over HPV16 in cases of adenocarcinoma in this region was contrasting to that of earlier Indian studies suggesting research on HPV18 related cervical carcinogenesis. PCR and DNA-sequencing could prove to be highly effective tools in HPV detection and genotyping. The study reported HPV16/18 infection in almost 98% of the cases, the knowledge about which might prove useful in future population based studies on HPV genotyping and designing of appropriate HPV-vaccines for this region.
