STAT3 is a key oncogenic transcription factor, often overactivated in several human cancers including hepatocellular carcinoma (HCC). STAT3 modulates the expression of genes that are connected with cell proliferation, antiapoptosis, metastasis, angiogenesis, and immune evasion in tumor cells. In this study, we investigated the effect of crocetin on the growth of HCC cells and dissected its underlying molecular mechanism in imparting a cytotoxic effect. Crocetin suppressed proliferation, promoted apoptosis, and counteracted the invasive capacity of HCC cells. Besides, crocetin downregulated the constitutive/inducible STAT3 activation (STAT3^Y705), nuclear accumulation of STAT3 along with suppression of its DNA binding activity in HCC cells with no effect on STAT5 activation. Crocetin suppressed the activity of upstream kinases such as Src, JAK1, and JAK2. Sodium pervanadate treatment terminated the crocetin-propelled STAT3 inhibition suggesting the involvement of tyrosine phosphatases. Crocetin increased the expression of SHP-1 and siRNA-mediated SHP-1 silencing resulted in the negation of crocetin-driven STAT3 inhibition. Further investigation revealed that crocetin treatment inhibited the expression of STAT3 regulated genes (Bcl-2, Bcl-xL, cyclin D1, survivin, VEGF, COX-2, and MMP-9). Taken together, this report presents crocetin as a novel abrogator of the STAT3 pathway in HCC cell lines.

中文翻译：

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藏红花素通过抑制 STAT3 信号传导在肝细胞癌中发挥抗增殖活性

STAT3 是一种关键的致癌转录因子，通常在包括肝细胞癌 (HCC) 在内的几种人类癌症中过度激活。STAT3 调节与肿瘤细胞中的细胞增殖、抗凋亡、转移、血管生成和免疫逃避相关的基因的表达。在这项研究中，我们研究了藏红花素对 HCC 细胞生长的影响，并剖析了其在赋予细胞毒性作用方面的潜在分子机制。Crocetin 抑制增殖，促进细胞凋亡，并抵消 HCC 细胞的侵袭能力。此外，藏红花素下调组成型/诱导型 STAT3 活化（STAT3 ^Y705)，STAT3 的核积累以及 HCC 细胞中其 DNA 结合活性的抑制对 STAT5 活化没有影响。Crocetin 抑制上游激酶如 Src、JAK1 和 JAK2 的活性。过钒酸钠处理终止了藏红花素推动的 STAT3 抑制，表明酪氨酸磷酸酶的参与。Crocetin 增加了 SHP-1 的表达，并且 siRNA 介导的 SHP-1 沉默导致了 crocetin 驱动的 STAT3 抑制的否定。进一步的研究表明，藏红花素处理抑制了 STAT3 调节基因（Bcl-2、Bcl-xL、cyclin D1、survivin、VEGF、COX-2 和 MMP-9）的表达。总之，本报告将藏红花素作为 HCC 细胞系中 STAT3 途径的一种新的消除剂。