The xenobiotic transporter ABCC4/MRP4 promotes epithelial mesenchymal transition in pancreatic cancer.

The xenobiotic transporter ABCC4/MRP4 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and correlates with a more aggressive phenotype and metastatic propensity. Here, we show that ABCC4 promotes epithelial-mesenchymal transition (EMT) in PDAC, a hallmark process involving the acquisition of mesenchymal traits by epithelial cells, enhanced cell motility, and chemoresistance. Modulation of ABCC4 levels in PANC-1 and BxPC-3 cell lines resulted in the dysregulation of genes present in the EMT signature. Bioinformatic analysis on several cohorts including tumor samples, primary patient-derived cultured cells, patient-derived xenografts, and cell lines, revealed a positive correlation between ABCC4 expression and EMT markers. We also characterized the ABCC4 cistrome and identified four candidate clusters in the distal promoter and intron one that showed differential binding of pro-epithelial FOXA1 and pro-mesenchymal GATA2 transcription factors in low ABCC4-expressing HPAF-II and high ABCC4-expressing PANC-1 xenografts. HPAF-II xenografts showed exclusive binding of FOXA1, and PANC-1 xenografts exclusive binding of GATA2, at ABCC4 clusters, consistent with their low and high EMT phenotype respectively. Our results underscore ABCC4/MRP4 as a valuable prognostic marker and a potential therapeutic target to treat PDAC subtypes with prominent EMT features, such as the basal-like/squamous subtype, characterized by worse prognosis and no effective therapies.

Multidrug transporter MRP4/ABCC4 as a key determinant of pancreatic cancer aggressiveness.

Recent findings show that MRP4 is critical for pancreatic ductal adenocarcinoma (PDAC) cell proliferation. Nevertheless, the significance of MRP4 protein levels and function in PDAC progression is still unclear. The aim of this study was to determine the role of MRP4 in PDAC tumor aggressiveness. Bioinformatic studies revealed that PDAC samples show higher MRP4 transcript levels compared to normal adjacent pancreatic tissue and circulating tumor cells express higher levels of MRP4 than primary tumors. Also, high levels of MRP4 are typical of high-grade PDAC cell lines and associate with an epithelial-mesenchymal phenotype. Moreover, PDAC patients with high levels of MRP4 depict dysregulation of pathways associated with migration, chemotaxis and cell adhesion. Silencing MRP4 in PANC1 cells reduced tumorigenicity and tumor growth and impaired cell migration. Transcriptomic analysis revealed that MRP4 silencing alters PANC1 gene expression, mainly dysregulating pathways related to cell-to-cell interactions and focal adhesion. Contrarily, MRP4 overexpression significantly increased BxPC-3 growth rate, produced a switch in the expression of EMT markers, and enhanced experimental metastatic incidence. Altogether, our results indicate that MRP4 is associated with a more aggressive phenotype in PDAC, boosting pancreatic tumorigenesis and metastatic capacity, which could finally determine a fast tumor progression in PDAC patients.

[Proximal femoral fractures: risk factors, bone mineral density, body composition and biochemical changes in and age-matched patients and controls]. / Fracturas del fémur proximal: factores de riesgo, densidad mineral osea, composición corporal y alteraciones bioquímicas en pacientes y controles de similar edad.

During one year (6/93-5/94) we performed a prospective study in patients with hip fracture, treated at the Hospital de Clínicas. A total of 102 women 52 to 94 years of age (Mean +/- 1SD: 79.5 +/- 9.1 years) and 17 men 61 to 98 years of age (79.7 +/- 9.9 years) who had sustained a hip fracture due to mild or moderate trauma were included. The ratio women: men was 6:1. We also studied 55 age-matched control women without diseases that could affect the skeleton or previous hip fracture (77.1 +/- 5.8 years of age). We did not study a control group in men. Women with hip fractures had lower weight (p < 0.01), lower age of onset of the menopause (p < 0.01) and a tendency to have with a greater frequency a mother with hip fracture (p < 0.08) compared with age-matched controls. When vertebral fractures were excluded, 44% of the hip fracture women had sustained previous skeletal fractures, while only 16% of the age-matched controls had suffered previous skeletal fractures (p < 0.001) (Table 2). The most frequent previous skeletal fractures were wrist and humerus. Forty eight percent of hip fracture women had had at least one vertebral fracture. About 17% of the hip fractured men had sustained previous skeletal fractures, while 5/12 men had suffered at least one vertebral fracture. Hip fractured women and men sustained greater history of diseases which provoke postural instability (Table 3). Biochemical determinations showed significantly diminished levels of serum albumin (p < 0.001) and calcium (p < 0.01), and increased serum PTH (p < 0.05) compared to age-matched controls (Table 4). Bone mineral density (determined by dual energy X-ray absorptiometry) was significantly diminished over proximal femur, total skeleton, legs and pelvis (p < 0.001), head and spine (p < 0.05) (Table 5). Body composition measurements showed that hip fracture women had a significantly lower lean mass compared with controls (p < 0.05). Fat mass also was lower in fracture patients compared with controls, but the difference was not statistically significant (Table 5). We conclude that hip fracture in our population is related to several previous factors: earlier onset of menopause, lower nutrition and body weight, previous diseases that increase the likelihood of falling, increased levels of PTH and reduced bone mass. Prevention of hip fractures should take into account all these factors, specially those that could be modified.

Bone mineral density in patients with cervical and trochanteric fractures of the proximal femur.

The bone mineral density (BMD) of the proximal femur, spine and radius shaft was determined in 75 women with atraumatic fractures of the proximal femur (FXf) (average age: 70.1 +/- 9.6 years) and 51 controls of similar age. Fractures were classified as either cervical (n = 36) or trochanteric (n = 39) on the basis of radiographic and surgical finding. The BMD of spine and proximal femur was determined by dual-photon absorptiometry (Lunar DP3) and the BMD of the radius shaft by single photon absorptiometry. The BMD of patients with FXf was significantly decreased over all skeletal sites compared to controls of similar age. No significant correlation was found between age and the BMD of the femoral neck in patients with FXf. Patients with trochanteric FXf were older and thinner (average: age, 72.9 +/- 9.4 years; weight, 53.1 +/- 7.8 kg) compared with patients with cervical fractures (age, 67.2 +/- 8.9 years; weight, 59.3 +/- 8.3 kg). Likewise the BMD of trochanteric FXf was lower at all measured sites: femoral neck, 0.548 +/- 0.066 g/cm2 vs 0.624 +/- 0.055 g/cm2 (P less than 0.001); L2-L4, 0.799 +/- 0.115 g/cm2 vs 0.925 +/- 0.106 g/cm2 (P less than 0.001); radius shaft, 0.454 +/- 0.057 g/cm2 vs 0.502 +/- 0.083 g/cm2 (P less than 0.05). Of the patients with trochanteric fractures 66% had concomitant vertebral fractures, while this occurred in only 28% of the patients with cervical fractures (P (Fisher) = 0.0007). In summary, females with trochanteric FXf are older, thinner, have less bone mass in all measured sites and suffer with a significantly greater frequency of vertebral fractures.(ABSTRACT TRUNCATED AT 250 WORDS)