Journal of Gastroenterology and Hepatology

Volume 34, Issue 10 pp. 1766-1776

Experimental Gastroenterology

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

Zhiming Jin,

Zhiming Jin

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

Zhiming Jin and Guoliang Zhang contributed equally to this work.Search for more papers by this author

Guoliang Zhang,

Guoliang Zhang

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

Zhiming Jin and Guoliang Zhang contributed equally to this work.Search for more papers by this author

Yiwen Liu,

Yiwen Liu

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

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Yiqing He,

Yiqing He

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

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Cuixia Yang,

Cuixia Yang

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

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Yan Du,

Yan Du

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

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Feng Gao,

Corresponding Author

Feng Gao

[email protected]

orcid.org/0000-0002-3456-722X

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

Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China

Correspondence

Dr Feng Gao, Department of Molecular Biology and Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.

Email: [email protected]

Search for more papers by this author

Zhiming Jin,

Zhiming Jin

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

Zhiming Jin and Guoliang Zhang contributed equally to this work.Search for more papers by this author

Guoliang Zhang,

Guoliang Zhang

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

Zhiming Jin and Guoliang Zhang contributed equally to this work.Search for more papers by this author

Yiwen Liu,

Yiwen Liu

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

Search for more papers by this author

Yiqing He,

Yiqing He

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

Search for more papers by this author

Cuixia Yang,

Cuixia Yang

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

Search for more papers by this author

Yan Du,

Yan Du

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

Search for more papers by this author

Feng Gao,

Corresponding Author

Feng Gao

[email protected]

orcid.org/0000-0002-3456-722X

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

Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China

Correspondence

Dr Feng Gao, Department of Molecular Biology and Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.

Email: [email protected]

Search for more papers by this author

First published: 14 March 2019

https://doi.org/10.1111/jgh.14660

Citations: 19

Declaration of conflict of interest: All the authors declare that they have no conflicts of interest.

Financial support: This work was funded by the National Natural Science Foundation of China (81702852, 81502491, 81572821, 81502490, and 81672843), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20171924), and the Program of Shanghai Leading Talents (2013-038).

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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.

Supporting Information

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Description

jgh14660-sup-0001-DataS1.docxWord 2007 document , 415.7 KB

Table S1. Histological type and grade of study subjects.

Figure S1. The mRNA expression levels of HYAL1 and HYAL2 in colon cancer cells. Real-time PCR was used to verify the knockdown or overexpression of HYAL1/2. A and B: When HYAL1 or HYAL2 was down-regulated, the mRNA levels of HYAL1 and HYAL2 were significantly decreased in LOVO and HCT116 cells. C and D: After HYAL1 or HYAL2 was overexpressed, the mRNA levels of HYAL1 and HYAL2 were significantly increased in LOVO and HCT116 cells. Bars represent mean ± SEM values. Statistically significant differences were determined using the Unpaired t test. **P < 0.01, ***P < 0.001.

Figure S2. The effects of HYAL1 and HYAL2 on the proliferation of colon cancer cells. After down-regulation or overexpression of HYAL1 and HYAL2, the proliferation of colon cancer cells was evaluated by CCK-8 assay. A: knockdown of HYAL1 or HYAL2 has no effects on the proliferative ability of LOVO and HCT116 cells. B: The proliferation of LOVO and HCT116 cells was also not influenced by the overexpression of HYAL1 or HYAL2. Bars represent mean ± SEM values. Statistically significant differences were determined using the Unpaired t test.

Figure S3. Analysis of HYAL1 and HYAL2 using a TCGA data of colon cancer. The data of 435 samples, including 39 normal subjects and 396 cancer subjects, were downloaded from the TCGA (The Cancer Genome Atlas) database and analyzed. A: The mRNA levels of HYAL1 and HYAL2 in normal subjects (n = 39) and colon cancer patients (n = 396). Both HYAL1 and HYAL2 levels were significantly higher in cancer tissues compared to normal controls. Bars represent mean ± SD values. Statistically significant differences were determined using the Mann Whitney test. ***P < 0.001. B: Kaplan–Meier survival analysis was made in 382 colon cancer patients with available follow-up data. The overall survival rate in colon cancer patients with high HYAL1 expression (n = 191) was significantly higher than that for those with low HYAL1 expression (n = 191) (>111.8 vs <111.8, P = 0.0004, log-rank test). The overall survival rate of colon cancer patients with high HYAL2 expression (n = 191) was also higher, but the difference was not statistically significant (>1962 vs <1962, P = 0.5257, log-rank test).

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Volume34, Issue10

October 2019

Pages 1766-1776

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

Abstract

Background

Methods

Results

Conclusions

Supporting Information

References

Citing Literature

References

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

Abstract

Background

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Supporting Information

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