HYAL1 和 HYAL2 在结直肠癌转移中的抑制作用。

The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer.

机构信息

Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Department of Molecular Biology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

出版信息

J Gastroenterol Hepatol. 2019 Oct;34(10):1766-1776. doi: 10.1111/jgh.14660. Epub 2019 Apr 10.

DOI:10.1111/jgh.14660

PMID:30972813

Abstract

BACKGROUND

Hyaluronidases (HAases), enzymes that degrade hyaluronan, have been widely investigated in cancer biology. However, whether HAases serve as tumor promoters or suppressors has been controversial in different cancers, and the exact role of HAases in colorectal cancer (CRC) has not been elucidated.

METHODS

The expression levels of HYAL1, HYAL2, and HYAL3 in cancer and corresponding normal tissues from CRC patients were examined via immunohistochemistry. Then the correlation between HAases levels and pathological characteristics of CRC patients was analyzed. To verify the clinical data, HYAL1 and HYAL2 were downregulated or overexpressed in colon cancer cells LOVO and HCT116 to observe their influences on cell invasion and migration. For the mechanism study, we investigated the effects of HYAL1 and HYAL2 on the expression of matrix metalloproteases (MMPs)/tissue inhibitor of metalloproteases (TIMPs) and distribution of F-actin.

RESULTS

All the three HAases were abnormally elevated in cancer tissues. Interestingly, HYAL1 and HYAL2, but not HYAL3, were negatively correlated with lymphatic metastasis and TNM stage. When HYAL1 and HYAL2 were knocked down, the invasion and migration abilities of colon cancer cells were accelerated, whereas overexpression of HYAL1 and HYAL2 had the opposite effects. In addition, colon cancer cells with HYAL1 and HYAL2 downregulation showed increased levels of MMP2 and MMP9, decreased levels of TIMP1 and TIMP2, and more intense F-actin stress fibers.

CONCLUSIONS

Our study suggests that HYAL1 and HYAL2 suppress CRC metastasis through regulating MMPs/TIMPs balance and rearranging F-actin distribution, further inhibiting invasion and migration of cancer cells.

摘要

背景

透明质酸酶（HAases）是一种能够降解透明质酸的酶，在癌症生物学中得到了广泛的研究。然而，HAases 在不同癌症中是作为肿瘤促进剂还是抑制剂存在一直存在争议，其在结直肠癌（CRC）中的确切作用尚未阐明。

方法

通过免疫组织化学检测 CRC 患者癌组织和相应正常组织中 HYAL1、HYAL2 和 HYAL3 的表达水平。然后分析 HAases 水平与 CRC 患者病理特征之间的相关性。为了验证临床数据，我们在 LOVO 和 HCT116 结肠癌细胞中下调或过表达 HYAL1 和 HYAL2，观察它们对细胞侵袭和迁移的影响。为了进行机制研究，我们研究了 HYAL1 和 HYAL2 对基质金属蛋白酶（MMPs）/金属蛋白酶组织抑制剂（TIMPs）表达和 F- 肌动蛋白分布的影响。

结果

三种 HAases 在癌组织中均异常升高。有趣的是，HYAL1 和 HYAL2，但不是 HYAL3，与淋巴转移和 TNM 分期呈负相关。当 HYAL1 和 HYAL2 被敲低时，结肠癌细胞的侵袭和迁移能力加快，而过表达 HYAL1 和 HYAL2 则产生相反的效果。此外，下调 HYAL1 和 HYAL2 的结肠癌细胞中 MMP2 和 MMP9 水平升高，TIMP1 和 TIMP2 水平降低，F-肌动蛋白应力纤维更强烈。