Ultraviolet light-induced collagen degradation inhibits melanoma invasion.

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.

Female Immunity Protects from Cutaneous Squamous Cell Carcinoma.

PURPOSE: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation. EXPERIMENTAL DESIGN: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing. RESULTS: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. CONCLUSIONS: This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.

Effect of a peer-led intervention combining mental health promotion with coping-strategy-based workshops on mental health awareness, help-seeking behavior, and wellbeing among university students in Hong Kong.

BACKGROUND: The psychological well-being of university students is an important factor in successfully coping with the demands of academic life. This study aimed to assess the impact of a peer-led intervention of mental health promotion combined with coping-strategy-based group workshops on mental health awareness and help-seeking behavior among university students in Hong Kong. METHOD: A mixed-method concurrent design was used for this study. Quantitative data, based on one-group pretest-posttest design, were collected using Mental Health Knowledge Schedule Questionnaire to assess mental health awareness, and Attitude Towards Seeking Professional Help Questionnaire-Short Form to examine help-seeking behavior of university students from The Hong Kong Polytechnic University. Qualitative data were collected from written post-activity reflections and focus group discussions which were thematically analyzed. RESULTS: A total of 62 university students (mean age: 23.2 ± 5.1 years) were included in this study. Mental health awareness was significantly improved (p = 0.015, 95% Confidence Interval of - 2.670, - 0.297) after program implementation. Help-seeking behavior mean score increased from pretest to posttest, however, no significant difference was observed (p = 0.188, 95% CI = - 1.775, 0.355). Qualitative analysis revealed that the program helped participants learn about coping strategies to help themselves and others with mental health challenges. CONCLUSIONS: The peer-led intervention provided a positive impact through increased mental health awareness and knowledge of coping strategies on self-help and helping others among university students. Further study could focus on the impact of the program when applied regularly throughout the entire academic year.

Emerging role of fatty acid binding proteins in cancer pathogenesis.

Fatty acid binding proteins (FABPs) are 15-kDa proteins responsible for the transport of fatty acids both intracellularly and extracellularly. Consisting of 12 different isoforms, some of the proteins have been found to be released in the serum and to be correlated with various diseases including cancer. Differential expression of these proteins has been reported to result in cancer pathogenesis by modulating various cancer signaling pathways; hence, in this review, we present the recent studies that have investigated the roles of different kinds of FABPs in different types of cancer and any possible underlying mechanisms to better understand the role of FABPs in cancer progression.

IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma.

Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver TIC properties, including self-renewal, tumorigenicity, and liver TIC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver TIC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced TIC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.Significance: IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway regulates cancer stemness and drug resistance and may be a novel therapeutic target in HCC. Cancer Res; 78(9); 2332-42. ©2018 AACR.