BackgroundHepatocellular carcinoma possesses a notable sex difference in incidence, and a protective role of estrogens has been hypothesized.MethodsUsing data from 13 cancer registries in the Surveillance, Epidemiology, and End Results Program, we describe the age-specific sex difference in the incidence of hepatocellular carcinoma in the United States during 1992-2013. We used a curve fitting by non-linear regression to quantitatively characterize the age-specific incidence rate of hepatocellular carcinoma by sex.ResultsA total of 44,287 incident cases of hepatocellular carcinoma (33,196 males and 11,091 females) were included, with an overall male-to-female ratio in age-standardized rate of 3.55. The sex ratio was below 2 at ages <25 years, increased with age from ages 25-29 years until peaking at 5.40 at ages 50-54 years, and declined thereafter. We also observed additional peaks in the age-specific sex ratio curves at ages 25-34 years across racial/ethnic groups. Modelling of age-specific incidence rates indicated a 15-year delayed increase with age in females compared with males in Asian and Pacific Islanders, and an 11-year delay in Hispanic whites.ConclusionsThe age-dependent patterns in the sex difference in the incidence of hepatocellular carcinoma support the hypothesis of a protective role of estrogens. The underlying reasons for the sex difference in hepatocellular carcinoma remain to be further explored in analytic epidemiological studies.

BackgroundHematological and neurological expressed 1 (HN1) is upregulated in many tumors, but the role of HN1 in breast cancer progression and its regulatory mechanism have not been well understood.MethodsTo study the role of HN1 in the initiation and progression of breast cancer, we examined HN1 levels in breast cancer cells and tissues and analyzed the relationship between HN1 levels and patient survival. We used mammosphere formation assay, side population analysis, wound healing assay, transwell assay, soft agar formation assay, and xenografted tumor model to determine the effect of HN1 on the expansion of breast cancer stem cells, and the migration, invasion and tumorigenesis of breast cancer. To determine whether HN1 regulates MYC, we used quantitative real-time PCR and Western blot analysis to assess the expression of MYC and their targeted genes to determine the phenotype caused by knockdown of MYC in breast cancer cell with HN1 overexpression.ResultsIn this study, we found that HN1 was upregulated in breast cancer tissues. Patients with high levels of HN1 expression had significantly shorter survival than those with low HN1 expression. In breast cancer cell line, ectopic overexpression of HN1 not only promoted the expansion of breast cancer stem cells, but also promoted cell migration, invasion, and tumorigenesis, while knockdown of HN1 reduced these effects. Furthermore, there was a positive correlation between MYC (also known as c-MYC) level and HN1 level, mechanism analysis suggested HN1 promoted the expression of MYC and its targeted genes like CDK4, CCND1, p21, CAV1, and SFRP1. Downregulation of MYC abrogated the effect of HN1 overexpression in breast cancer cell lines.ConclusionTaken together, these data reveal that HN1 promotes the progression of breast cancer by upregulating MYC expression, and might be a therapeutic target for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0656-1) contains supplementary material, which is available to authorized users.

Pancreatic ductal adenocarcinoma (PDAC), which accounts for 96% of all pancreatic cancer cases, is characterized by rapid progression, invasion and metastasis. Transforming growth factor-beta (TGF-β) signaling is an essential pathway in metastatic progression and microRNAs (miRNA) play central roles in the regulation of various biological and pathologic processes including cancer metastasis. However, the molecular mechanisms involved in regulation of miRNAs and activation of TGF-β signaling in PDAC remain to be established. The results of this study suggested that miR-323-3p expression in PDAC tissues and cell lines was significantly decreased compared to levels in normal pancreatic tissues and primary cultured pancreatic duct epithelial cells. Further investigation revealed that miR-323-3p directly targeted and suppressed SMAD2 and SMAD3, both key components in TGF-β signaling. Lower levels of miR-323-3p predicted poorer prognosis in patients with PDAC. Ectopic overexpression of miR-323-3p significantly inhibited, while silencing of miR-323-3p increased the migration and invasion abilities of PDAC cells in vitro. Moreover, using an in vivo mouse model, we demonstrated that overexpressing of miR-323-3p significantly reduced, while knockdown of miR-323-3p enhanced lung metastatic colonization of PANC-1 cells. Furthermore, miR-323-3p-induced TGF-b signaling inhibition and cell motility suppression were partially rescued by overexpressing of Smad2 and Smad3 in PDAC cells. Our findings suggest that re-expression of miR-323-3p might offer a novel therapeutic target against metastasis in patients with PDAC.

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HER2 amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110α or p110β inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2-activation and Pten-loss coupled with deletion of p110α or p110β. Ablation of p110α, but not p110β, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110α primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110β conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110α inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110β inhibitor to dual HER2 and p110α inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110α/β may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors.

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Lysine crotonylation is a recently discovered post-translation modification involved in transcription regulation, cell signal transduction, and other processes. Scientists have identified several crotonylases and decrotonylases of histones, including P300/CBP, HDACs, and SIRTs. However, the regulation of non-histone protein crotonylation remains unclear. In the current study, we verified that crotonylation was upregulated in hypoxia and promoted liver cancer cell growth. We performed TMT-labeled quantitative lysine crotonylome analysis in 12 pairs of hepatocellular carcinoma and adjacent liver tissue and identified 3,793 lysine crotonylation sites in 1,428 proteins. We showed that crotonylation of lamin A at the site of K265/270 maintains its subcellular position, promotes liver cancer cell proliferation, and prevents cellular senescence. Our data indicate that HDAC6 is the decrotonylase of lamin A and downregulated in response to hypoxia, resulting in lamin A K265/270cr. Taken together, our study reveals the lamin A crotonylation in liver cancer progression and fills the research gap in non-histone protein crotonylation function.