Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in ...PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. These findings uncover a pivotal role for SMYD2 in promoting pancreatic cancer.
The p53 protein is expressed as multiple isoforms that differ in their N- and C-terminus due to alternative splicing, promoter or codon initiation usage. Δ40p53 lacks the first 39 residues containing ...the main transcriptional activation domain, resulting from initiation of translation at AUG +40 in fully spliced p53 mRNA or in a specific variant mRNA retaining intron 2. Overexpression of Δ40p53 antagonizes wild-type p53 in vitro. However, animal models of Δ40p53 in mouse or Zebrafish have shown complex phenotypes suggestive of p53-dependent growth suppressive effects.
We have co-transfected expression vectors for p53 and Δ40p53 in p53-null cell lines Saos-2 and H1299 to show that Δ40p53 forms mixed oligomers with p53 that bind to DNA and modulate the transcription of a generic p53-dependent reporter gene.
In H1299 cells, co-expression of the two proteins induced a decrease in transcription with amplitude that depended upon the predicted composition of the hetero-tetramer. In Saos-2, a paradoxical effect was observed, with a small increase in activity for hetero-tetramers predicted to contain 1 or 2 monomers of Δ40p53 and a decrease at higher Δ40p53/p53 ratios. In this cell line, co-transfection of Δ40p53 prevented Hdm2-mediated degradation of p53.
Δ40p53 modulates transcriptional activity by interfering with the binding of Hdm2 to hetero-tetramers containing both Δ40p53 and p53. These results provide a basis for growth suppressive effects in animal models co-expressing roughly similar levels of p53 and Δ40p53.
To investigate the clinical value of somatic TP53 mutations in breast cancer, we assembled clinical and molecular data on 1,794 women with primary breast cancer with long-term follow-up and whose ...tumor has been screened for mutation in exons 5 to 8 of TP53 by gene sequencing. TP53 mutations were more frequent in tumors of ductal and medullar types, aggressive phenotype (high grade, large size, node positive cases, and low hormone receptor content) and in women <60 years old. TP53 mutations within exons 5 to 8 conferred an elevated risk of breast cancer-specific death of 2.27 (relative risk >10 years; P < 0.0001) compared with patients with no such mutation. The prognostic value of TP53 mutation was independent of tumor size, node status, and hormone receptor content, confirming and reconciling previous findings in smaller series. Moreover, an interaction between TP53 mutation and progesterone receptor (PR) status was revealed, TP53 mutation combined with the absence of progesterone receptor being associated with the worst prognosis. Whereas previous studies have emphasized the fact that missense mutations in the DNA-binding motifs have a worse prognosis than missense mutations outside these motifs, we show that non-missense mutations have prognostic value similar to missense mutations in DNA-binding motifs. Nonetheless, specific missense mutants (codon 179 and R248W) seem to be associated with an even worse prognosis. These results, obtained on the largest series analyzed thus far, show that TP53 mutations identified by gene sequencing have an independent prognostic value in breast cancer and could have potential uses in clinical practice.
Summary Among the 278 092 publications indexed into PubMed in 1979, a handful of articles stand out as the foundation of one of the most profound forays into the molecular basis of carcinogenesis: ...the discovery of the p53 tumour-suppressor protein. In the 30 years since then, understanding of p53 has progressed from obscure oncogene to key tumour-suppressor gene with clinical potential. Yet, p53 research has not followed a straight course. In this Historical Review, we describe how the 1979 discovery has shaped our view of the molecular basis of cancer, and identify some crucial steps ahead to transfer the wealth of knowledge accumulated on p53 into applications to cancer prevention and treatment.
Abstract There are approximately 360 millions chronic carriers of Hepatitis B virus worldwide. Patterns of HB carriage are variable from one region to the other. Regions with rates of carriage over ...8% are commonly considered as “high endemicity” regions. HB carriers have a very significant lifetime risk of developing chronic liver diseases such as cirrhosis and/or liver cancer (hepatocellular carcinoma, HCC). An efficient HB vaccine is available since the early eighties and has been used since for universal infant vaccination in regions of high endemicity. Observations from Taiwan, where universal infant vaccination was introduced from 1984, show a remarkable, long-lasting protection against carriage and reduction of HCC rates in adolescent and young adults born after the initiation of the programme. Two population-based trials have been set up in the mid-eighties to evaluate lifelong protective effects of infant HB vaccine against liver cancer, in The Gambia (West Africa) and in the area of Qidong, China. In other high-endemicity regions of Asia and Africa, universal infants vaccination has consistently showed a long-lasting high protection against chronic carriage and this is expected to lead to a dramatic decrease of chronic liver disease and liver cancer within the next decades. Here we briefly review the lessons of vaccination programmes and trials in high-endemicity regions, based on data gathered during 15–20 years of implementation.
Circulating cell-free DNA (cfDNA) is emerging as a potential tumor biomarker. CfDNA-based biomarkers may be applicable in tumors without an available non-invasive screening method among at-risk ...populations. Esophageal squamous cell carcinoma (ESCC) and residents of the Asian cancer belt are examples of those malignancies and populations. Previous epidemiological studies using cfDNA have pointed to the need for high volumes of good quality plasma (i.e., >1 mL plasma with 0 or 1 cycles of freeze-thaw) rather than archival serum, which is often the main available source of cfDNA in retrospective studies. Here, we have investigated the concordance of
mutations in tumor tissue and cfDNA extracted from archival serum left-over from 42 cases and 39 matched controls (age, gender, residence) in a high-risk area of Northern Iran (Golestan). Deep sequencing of
coding regions was complemented with a specialized variant caller (Needlestack). Overall, 23% to 31% of mutations were concordantly detected in tumor and serum cfDNA (based on two false discovery rate thresholds). Concordance was positively correlated with high cfDNA concentration, smoking history (
-value = 0.02) and mutations with a high potential of neoantigen formation (OR; 95%CI = 1.9 (1.11-3.29)), suggesting that tumor DNA release in the bloodstream might reflect the effects of immune and inflammatory context on tumor cell turnover. We identified
mutations in five controls, one of whom was subsequently diagnosed with ESCC. Overall, the results showed that cfDNA mutations can be reliably identified by deep sequencing of archival serum, with a rate of success comparable to plasma. Nonetheless, 70% non-identifiable mutations among cancer patients and 12% mutation detection in controls are the main challenges in applying cfDNA to detect tumor-related variants when blindly targeting whole coding regions of the
gene in ESCC.
The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some ...indication that long-term stem-cell viability may require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p53 protein, epigenetic stability is enforced and stem-cell replication is regulated by commitment to differentiation. Over a lifetime of an organism, stem-cell clones compete in a tissue niche for Darwinian replicative advantages and in doing so accumulate mutations that permit stem-cell replication. Mutations in the p53 gene give stem cells this advantage, increase the clonal stem-cell population, and lower the age at which cancers can occur. Li-Fraumeni patients that inherit p53 mutations develop tumors in a tissue-type-specific fashion at younger ages. Throughout the life of a Li-Fraumeni patient, the tumor types that arise occur in tissues where stem cells are active and cell division is most rapid. Thus, p53 mutations that are inherited or occur during developmental life act in stem cells of the mesenchymal and epithelial lineages, whereas p53 mutations that occur in progenitor or differentiated (somatic) cells later in life function in tissues of endodermal origins, indicating that p53 may function differently in different developmental lineages.
A nationwide childhood programme started in The Gambia in 1986 showed that the inclusion of the vaccine against HBV in WHO's Expanded Programme on Immunization induced long-term protection against ...chronic carriage of HBV even without a booster.67 Interventions to reduce aflatoxin exposure after harvest in rural Guinea have led to less contamination of food stores and individuals' exposure.8 However, despite formal policies for vaccination against HBV by many countries and support from the GAVI Alliance, overall coverage of infants with HBV vaccine in sub-Saharan Africa remains worringly low,9 and aflatoxin contamination remains unabated,10 mainly due to economic and logistical constraints. The plan should include at least: (1) a sustainable childhood HBV vaccination strategy throughout the continent; (2) a reduction in dietary exposure to aflatoxin; (3) monitoring and understanding of the spread of HCV and interactions with HIV/AIDS; and (4) registration and early detection of cases of cancer as crucial steps towards appropriate clinical interventions.
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