Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell death induced by a variety of stress stimuli, such as tumor necrosis factor, UV radiation, and chemotherapeutic drug treatment. Loss of WWOX gene expression due to gene deletions, loss of heterozygosity, chromosomal translocations, or epigenetic silencing is frequently observed in human malignant cancer cells. Acquisition of chemoresistance in squamous cell carcinoma, osteosarcoma, and breast cancer cells is associated with WWOX deficiency. WWOX protein physically interacts with many signaling molecules and exerts its regulatory effects on gene transcription and protein stability and subcellular localization to control cell survival, proliferation, differentiation, autophagy, and metabolism. In this review, we provide an overview of the recent advances in understanding the molecular mechanisms by which WWOX regulates cellular functions and stress responses. A potential scenario is that activation of WWOX by anticancer drugs is needed to overcome chemoresistance and trigger cancer cell death, suggesting that WWOX can be regarded as a prognostic marker and a candidate molecule for targeted cancer therapies.

Background: Previous studies have stated that high-income countries tend to have the highest incidence and mortality for all types of cancer, while geographical factors are also linked to the prevalence of cancer. Only a few studies have explored the relevance of economic/geographical factors to the cancer epidemic integrally. Aim: This study aims to explore the diversities of the overall cancer epidemic rates made by geographic and economic variations respectively and their interaction effects, after adjusting gender, population structure. Methods: We collected 170 countries' epidemic data from WHO's 2012 GLOBOCAN project and economic classifications data from the World Bank in 2012. We applied generalized linear model to make 2-way ANOVA and to analyze the variations of 3 epidemic rates (age-standardized incidence, age-standardized mortality and prevalence) between 6 regions (Asia, Africa, Europe, North America, South America, and Oceania) and 4 income levels (high income, upper-middle income, lower-middle income and low income). We identified extreme rates and discuss their reasons and implications, and make suggestions regarding the situations. Results: Both geographic variation and economic variation were key factors for incidence and prevalence of global cancer burden, and the interaction between geographic and economic variations on incidence and prevalence was very strong. However, there was no significant association between income and mortality, and the interaction between geographic and economic variations on mortality was not obvious either. Using South America as the reference, only North America had significant higher incidence rate of cancer; no significant variation of mortality rates between regions was observed; North America and Europe had significant higher prevalence rates. Using low income as the reference, only high and upper-middle income had significant higher incidence rates; no significant variation of mortality rates between regions was observed; only high income had significant higher prevalence rates. Among high-income countries, incidence, mortality and prevalence rates in Europe were significantly higher than them in South America, Asia and Africa. Among countries in Europe, high-income country had significantly higher incidence rate than that in upper-middle cancer, and it also had significant higher prevalence rates than them in upper-middle and lower-middle countries. Conclusion: Overall, the cancer incidence and prevalence are significantly different due to the country's geographical location and economic level, but the mortality rate is not. Understanding the differences in geographical location and economic levels between countries and their interactions on the cancer epidemic would benefit the future global cancer prevention and treatment policy planning.