Posterior HOX genes and HOTAIR expression in the proximal and distal colon cancer pathogenesis

Abstract Background Increasing evidences showed that the location of the primary tumor on the right (proximal) or left (distal) side of the colon have a prognostic/predictive value for colon cancer patients. However, the understanding of the molecular mechanisms that contribute to the pathogenesis in different location of colon is still unclear. Probably an important role could be played by genes that control the spatial–temporal development of bodily structures, such as HOX genes. Methods The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes and of the HOX regulating lncRNA HOTAIR in distal and proximal CRC cases. We have carried out a Tissue Micro Array with left and right CRC samples associated with all clinical-pathological parameters of patients. The expression of HOX genes was evaluated by immunohistochemistry and the staining of HOTAIR was performed by in situ hybridization using a specifically designed LNA probe. Results All paralogous 13 HOX genes and HOTAIR are silent in normal tissue and expressed in CRC samples. HOXB13, HOXC13 and HOTAIR showed a statistical association with lymph nodes metastasis (p value = 0.003, p value = 0.05, p value = 0.04). HOXB13, HOXC13 and lncRNA HOTAIR are overexpressed in right CRCs samples (p value < 0 and p value = 0.021). HOTAIR is also strongly correlated with HOXB13 (p value = 0.02) and HOXC13 (p value = 0.042) expression. Conclusions Our data highlighted an important role of posterior HOX genes in colorectal cancer carcinogenesis. Specifically, the aberrant expression of the HOXB13, HOXC13 and HOTAIR in proximal colon cancers could add an important dowel in understanding molecular mechanisms related to tumor pathogenesis in this location

Effect of long-term L-thyroxine treatment on bone mineral density in young adults with congenital hypothyroidism.

To evaluate whether long-term L-thyroxine therapy in young adults with congenital hypothyroidism may affect bone mineral density (BMD). Thirty-seven subjects with congenital hypothyroidism, detected by neonatal screening and longitudinally followed from the time of diagnosis and treatment (26+/-4 days) up to the age of 17.8+/-1.0 years, were studied. Spinal (L2-L4) BMD, measured by dual-energy X-ray densitometry, and bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) by quantitative ultrasound, were evaluated. Z-score mean values (+/-s.d.) of BMD (-0.3+/-0.7) and Ad-SoS (-0.7+/-1. 1) were slightly below the average but within the normal range. Ad-SoS resulted in a z-score below -1 in 38% of patients as compared with BMD which resulted in a z-score below -1 in only 13.5% of subject. No significant differences were observed between males (BMD, -0.3+/-0.7; Ad-SoS, -0.9+/-1.0) and females (BMD, -0.3+/-0.7; Ad-SoS, -0.5+/-1.2) or when dividing patients on the basis of aetiological defects; ectopic gland (BMD, -0.3+/-0.6; Ad-SoS, -0.8+/-0.9), athyreosis (BMD, -0.3+/-0.9; Ad-SoS, -0.8+/-1.0) and eutopic gland (BMD, -0.3+/-0.8; Ad-SoS, -0.4+/-1.3). No significant relationships were observed between BMD or Ad-SoS z-score and hormonal status or L-thyroxine dosages at the time of the study or during the pubertal period. The careful monitoring of serum thyroid-stimulating hormone and adjustment of l-thyroxine dosage avoided the significant deleterious effects of prolonged L-thyroxine replacement therapy on bone tissue in adolescents and young adults with congenital hypothyroidism treated from the neonatal period

Effects of long-term L-thyroxine treatment on endothelial function and arterial distensibility in young adults with congenital hypothyroidism.

OBJECTIVE: Patients with congenital hypothyroidism (CH) display subclinical abnormalities of the cardiovascular system that are related to unphysiological fluctuations of TSH levels and occur despite careful replacement therapy. DESIGN: The aim of the present case-control study was to evaluate the effects of long-term levothyroxine (l-T(4)) replacement therapy on the vascular district in CH patients by assessing endothelial function with flow-mediated dilation (FMD) and brachial artery distensibility with the measurement of the coefficient of distensibility (DC). METHODS: Thirty-two young adults with CH aged 18.9+/-0.2 years and 32 age- and sex-matched controls underwent brachial Doppler ultrasound examination to measure FMD and DC at the time of the study. Hypothyroidism was diagnosed by neonatal screening, and l-T(4) treatment was initiated within the first month of life. RESULTS: Compared to healthy controls, CH patients had significantly reduced brachial artery reactivity with lower FMD values (8.9+/-5.7 vs 14.1+/-5.1% P=0.003) and decreased vascular distensibility (24.6+/-1.6 vs 27.3+/-3 kPa(-1)x10(-3), P<0.0002). Linear regression analysis revealed that both total and pubertal mean TSH and number of episodes of undertreatment were independent determinants of FMD and DC. Pubertal mean TSH was the best predictor of both FMD and DC (r=0.81 and r=0.87 respectively, P<0.001). CONCLUSIONS: Young adults with CH treated with long-term l-T(4) replacement therapy may have significant impairment of both FMD and DC. Our data suggest that high TSH levels, inadequately corrected by l-T(4) replacement therapy in CH patients especially during puberty, can exert significant effects on the elastic and functional vessel properties

Long-term cardiovascular effects of levothyroxine therapy in young adults with congenital hypothyroidism.

Congenital hypothyroidism (CH) is the most prevalent endocrine disorder in the newborn and is routinely treated with life-long levothyroxine replacement therapy. Although several studies have demonstrated that such therapy may impact on the cardiovascular system, little is known with regard to the effects of long-term levothyroxine administration in patients with CH. The aim of the current study was to evaluate whether long-term levothyroxine replacement therapy in young adults with CH is associated with cardiovascular abnormalities. Thirty young adults with CH aged 18.1 +/- 0.2 yr and 30 age- and sex-matched controls underwent cardiac and carotid Doppler ultrasound and symptom-limited cardiopulmonary exercise testing. Hypothyroidism was diagnosed by neonatal screening, and levothyroxine treatment was initiated within the first month of life and carefully adjusted to maintain TSH levels in the normal range and free T(4) in the high-normal range.Compared with controls, hypothyroid patients exhibited left ventricular diastolic dysfunction, impaired exercise capacity, and increased intima-media thickness. At multiple regression analysis, the number of episodes of plasma TSH levels less than 0.5 mU/liter and greater than 4.0 mU/liter from the age of 1 yr onward, and mean TSH plasma levels during puberty were independent predictors of diastolic filling and cardiopulmonary performance indexes (multiple r values: 0.61-0.75). Long-term levothyroxine treatment in young adults with congenital hypothyroidism is associated with impaired diastolic function and exercise capacity and increased intima-media thickness