Mammalian cells evolve a delicate system, the DNA damage response (DDR) pathway, to monitor genomic integrity and to prevent the damage from both endogenous end exogenous insults. Emerging evidence suggests that aberrant DDR and deficient DNA repair are strongly associated with cancer and aging. Our understanding of the core program of DDR has made tremendous progress in the past two decades. However, the long list of the molecules involved in the DDR and DNA repair continues to grow and the roles of the new “dots” are under intensive investigation. Here, we review the connection between DDR and DNA repair and aging and discuss the potential mechanisms by which deficient DNA repair triggers systemic effects to promote physiological or pathological aging.

Vascular endothelial growth factor receptor 3 (VEGFR3) has been known for its involvement in tumor-associated lymphangiogenesis and lymphatic metastasis. The VEGFR3 signaling is stimulated by its main cognate ligand, vascular endothelial growth factor C (VEGF-C), which in turn promotes tumor progression. Activation of VEGF-C/VEGFR3 signaling in lymphatic endothelial cells (LECs) was shown to enhance the proliferation of LECs and the formation of lymphatic vessels, leading to increased lymphatic metastasis of tumor cells. In the past decade, the expression and pathological roles of VEGFR3 in tumor cells have been described. Moreover, the VEGF-C/VEGFR3 axis has been implicated in regulating immune tolerance and suppression. Therefore, the inhibition of the VEGF-C/VEGFR3 axis has emerged as an important therapeutic strategy for the treatment of cancer. In this review, we discuss the current findings related to VEGF-C/VEGFR3 signaling in cancer progression and recent advances in the development of therapeutic drugs targeting VEGF-C/VEGFR3.

Pancreatic cancer is poorly responsive to chemotherapy due to intrinsic or acquired resistance. Our previous study showed that epigenetic modifying enzymes including protein arginine methyltransferase 3 (PRMT3) are dysregulated in gemcitabine (GEM)-resistant pancreatic cancer cells. Here, we attempt to elucidate the role of PRMT3 in chemoresistance. Overexpression of PRMT3 led to increased resistance to GEM in pancreatic cancer cells, whereas reduction of PRMT3 restored GEM sensitivity in resistant cells. We identified a novel PRMT3 target, ATP-binding cassette subfamily G member 2 (ABCG2), which is known to play a critical role in drug resistance. PRMT3 overexpression upregulated ABCG2 expression by increasing its mRNA stability. Mass spectrometric analysis identified hnRNPA1 as a PRMT3 interacting protein, and methylation of hnRNPA1 at R31 by PRMT3 in vivo and in vitro. The expression of methylation-deficient hnRNPA1-R31K mutant reduced the RNA binding activity of hnRNPA1 and the expression of ABCG2 mRNA. Taken together, this provides the first evidence that PRMT3 methylates the RNA recognition motif (RRM) of hnRNPA1 and promotes the binding between hnRNPA1 and ABCG2 to enhance drug resistance. Inhibition of PRMT3 could be a novel strategy for the treatment of GEM-resistant pancreatic cancer.

Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between β1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of β1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of β1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of β1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in β1 integrin-depleted cells. Consistent to in vitro data, β1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, β1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that β1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival.

Cancer cell metastasis is the main cause of death in patients with cancer. Many studies have investigated the biochemical factors that affect metastasis; however, the role of physical factors such as fluid shear stress (FSS) in tumorigenesis and metastasis have been less investigated. Triple-negative breast cancer (TNBC) has a higher incidence of lymph node invasion and distant metastasis than other subtypes of breast cancer. In this study, we investigated the influence of FSS in regulating the malignant behavior of TNBC cells. Our data demonstrate that low FSS promotes cell migration, invasion, and drug resistance, while high FSS has the opposite results; additionally, we found that these phenomena were regulated through focal adhesion kinase (FAK). Using immunohistochemistry staining, we show that FAK levels correlate with the nodal stage and that FAK is a significant independent predictor of overall survival in patients. Altogether, these data implicate FAK as a fluid mechano-sensor that regulates the cell motility induced by FSS and provide a strong rationale for cancer treatments that combine the use of anti-cancer drugs and strategies to modulate tumor interstitial fluid flow.