FOXM1 augments sorafenib resistance and promotes progression of hepatocellular carcinoma by epigenetically activating KIF23 expression.

Sorafenib has been used to enhance the survival outcome of hepatocellular carcinoma (HCC) patients. But, occurrence resistance to sorafenib subtracts from its therapeutic benefits. Herein, we identified that FOXM1 was markedly upregulated in both tumor samples and sorafenib-resistant HCC tissues. We also demonstrated that patients with decreased FOXM1 expression had longer overall survival (OS) and progression-free survival (PFS) in the cohort of sorafenib-treated patients. For HCC cells resistant to sorafenib, the IC50 value of sorafenib and the expression of FOXM1 were increased. In addition, Downregulation of FOXM1 expression alleviated the occurrence of resistance to sorafenib and reduced the proliferative potential and viability of HCC cells. Mechanically, the suppression of the FOXM1 gene resulted in the downregulation of KIF23 levels. Moreover, downregulation of FOXM1 expression reduced the levels of RNA polymerase II (RNA pol II) and histone H3 lysine 27 acetylation (H3K27ac) on the KIF23 promoter, further epigenetically silencing the production of KIF23. More intriguingly, our results similarly revealed that FDI-6, a specific inhibitor of FOXM1, suppressed the proliferation of HCC cells resistant to sorafenib, as well as upregulation of FOXM1 or KIF23 abolished this effect. In addition, we found that FDI-6 combined with sorafenib significantly improved the therapeutic effect of sorafenib. Collectively, the present results revealed that FOXM augments sorafenib resistance and enhances HCC progression by upregulating KIF23 expression via an epigenetic mechanism, and targeting FOXM1 can be an effective treatment for HCC.

Long-term oncologic outcomes following breast cancer surgery in adolescents and young adults: a single-center retrospective analysis.

Background: Breast cancer (BC) in adolescents and young adults (AYAs, aged 15-39 years), remains inadequately understood. The incidence of BC in AYAs has been steadily increasing, making it the second leading cause of cancer-related mortality among females aged 0-39 globally. This study aimed to elucidate the clinical characteristics and long-term outcomes of AYAs and older adults (OAs, aged > 39 years) with BC who underwent surgery. Methods: From January 2011 to June 2017, BC patients who underwent surgery were enrolled in this study and divided into AYA group and OA group. Clinical characteristics, recurrence-free survival (RFS), and overall survival (OS) were compared between these two groups, both before and after propensity score matching (PSM). Univariate and multivariate Cox proportional hazard regression analyses were performed to assess the influence of age on OS and RFS. Results: Compared to the OA group, the AYA group exhibited a younger age at menarche (p < 0.001), a lower prevalence of menopausal status (p < 0.001), a reduced occurrence of comorbid conditions (p < 0.001), fewer instances of undergoing mastectomy (p = 0.031), a higher incidence of Triple-Negative Breast Cancer (TNBC) (p = 0.046), and elevated Ki-67 levels (p = 0.036). In terms of prognostic outcomes, within the study cohort, AYAs had a higher mortality rate and poorer long-term survival compared to OAs, both before and after PSM. In the PSM cohort, AYAs experienced a significantly shorter median OS (p < 0.001) and RFS (p < 0.001). Young age (15-39 years) emerged as an independent risk factor for OS (HR 2.659, 95% CI 1.385-5.106, p = 0.003) and RFS (HR 3.235, 95% CI 2.085-5.022, p < 0.001) in BC patients following surgery. Conclusion: Significant differences were identified in the clinicopathological characteristics between AYA and OA patients with BC. In comparison to OA patients, AYA patients exhibited a less favorable long-term prognosis, with young age emerging as an independent prognostic risk factor for both OS and RFS in BC patients following surgery. Further investigations are warranted to develop age-specific therapeutic approaches for AYA BC patients.