Nazmeen Aarifa, Maiti Sayantani, Maiti Smarajit
Department of Biochemistry, Cell and Molecular Therapeutics Lab, Oriental Institute of Science and Technology, Midnapore 721101, India.
Haldia Institute of Health Sciences, ICARE, Haldia, East Midnapore, India.
Genes Cancer. 2024 Aug 9;15:41-59. doi: 10.18632/genesandcancer.237. eCollection 2024.
In some breast cancers, altered estrogen-sulfotransferase (SULT1E1) and its inactivation by oxidative-stress modifies E2 levels. Parallelly, hypoxia-inducible tissue-damaging factors (HIF1α) are induced. The proteins/genes expressions of these factors were verified in human-breast-cancer tissues. SULT1E1 inducing-drugs combinations were tested for their possible protective effects.
Matrix-metalloproteases (MMP2/9) activity and SULT1E1-HIF1α protein/gene expression (Western-blot/RTPCR) were assessed in breast-cancers versus adjacent-tissues. Oxidant-stress neutralizer, chalcone (trans-1,3-diaryl-2-propen-1-ones) and SULT1E1-inducer pure dialyl-sulfide (garlic; ) were tested to prevent cancer causing factors in rat, and . The antioxidant-enzymes SOD1/catalase/GPx/LDH and matrix-degenerating MMP2/9 activities were assessed (gel-zymogram). Histoarchitecture (HE-staining) and tissue SULT1E1-localization (immuno-histochemistry) were screened. Extensive statistical-analysis were performed.
Human cancer-tissue expresses higher SULT1E1, HIF1α protein/mRNA and lower LDH activity. Increase of MMP2/9 activities commenced tissue damage. However, chalcone and DAS significantly induced SULT1E1 gene/protein, suppressed HIF1α expression, MMP2/9 activities in rat tissues. Correlation and group statistics of t-test suggest significant link of oxidative-stress (MDA) with SULT1E1 ( = 0.006), HIF1α ( = 0.006) protein-expression. The non-protein-thiols showed negative correlation ( = 0.001) with HIF1α. These proteins and SULT1E1-mRNA expressions were significantly higher in tumor ( < 0.05). Correlation data suggest, SULT1E1 is correlated with non-protein-thiols.
Breast cancers associate with SULT1E1, HIF1α and MMPs deregulations. For the first time, we are revealing that advanced cancer tissue with elevated SULT1E1-protein may reactivate in a reducing-state initiated by chalcone, but remain dormant in an oxidative environment. Furthermore, increased SULT1E1 protein synthesis is caused by DAS-induced mRNA expression. The combined effects of the drugs might decrease MMPs and HIF1α expressions. Further studies are necessary.
在某些乳腺癌中，雌激素硫酸转移酶（SULT1E1）改变及其被氧化应激失活会改变E2水平。同时，缺氧诱导的组织损伤因子（HIF1α）被诱导。在人乳腺癌组织中验证了这些因子的蛋白质/基因表达。测试了SULT1E1诱导药物组合的可能保护作用。
评估乳腺癌与相邻组织中基质金属蛋白酶（MMP2/9）活性以及SULT1E1-HIF1α蛋白质/基因表达（蛋白质印迹法/逆转录聚合酶链反应）。测试抗氧化应激剂查耳酮（反式-1,3-二芳基-2-丙烯-1-酮）和SULT1E1诱导剂纯二烯丙基硫醚（大蒜；）以预防大鼠体内的致癌因素。评估抗氧化酶超氧化物歧化酶1/过氧化氢酶/谷胱甘肽过氧化物酶/乳酸脱氢酶和基质降解MMP2/9活性（凝胶酶谱法）。筛选组织结构（苏木精-伊红染色）和组织SULT1E1定位（免疫组织化学）。进行广泛的统计分析。
人癌组织中SULT1E1、HIF1α蛋白质/信使核糖核酸表达较高，乳酸脱氢酶活性较低。MMP2/9活性增加引发组织损伤。然而，查耳酮和二烯丙基硫醚显著诱导大鼠组织中SULT1E1基因/蛋白质表达，抑制HIF1α表达、MMP2/9活性。相关性和t检验组统计表明氧化应激（丙二醛）与SULT1E1（P = 0.006）、HIF1α（P = 0.006）蛋白质表达有显著联系。非蛋白质硫醇与HIF1α呈负相关（P = 0.001）。这些蛋白质和SULT1E1信使核糖核酸表达在肿瘤中显著更高（P < 0.05）。相关性数据表明，SULT1E1与非蛋白质硫醇相关。
乳腺癌与SULT1E1、HIF1α和基质金属蛋白酶失调有关。我们首次揭示，SULT1E1蛋白升高的晚期癌组织可能在查耳酮引发的还原状态下重新激活，但在氧化环境中保持休眠。此外，二烯丙基硫醚诱导的信使核糖核酸表达导致SULT1E1蛋白合成增加。药物的联合作用可能降低基质金属蛋白酶和HIF1α表达。有必要进行进一步研究。
