<i><scp>MIIP</scp></i> haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer

Sun, Yan; Ji, Ping; Chen, Tao; Zhou, Xinhui; Yang, Da; Guo, Yuhong; Liu, Yuexin; Hu, Limei; Xia, Dianren; Liu, Yanxue; Multani, Asha S.; Shmulevich, Ilya; Kucherlapati, Raju; Kopetz, Scott; Sood, Anil K.; Hamilton, Stanley R.; Sun, Bei; Zhang, Wei

doi:10.1002/path.4823

Cited by 15 publications

(19 citation statements)

References 43 publications

(49 reference statements)

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“…In gliomas, through binding to HDAC6, highly expressed MIIP causes decreased HDAC6 expression and inhibition of HDAC6 deacetylase activity, thereby inhibiting HDAC6-mediated cell migration [19]. The tumor suppressor function of MIIP has been demonstrated in tissues from breast cancer [30] and colorectal cancer [31]. In the current study, we verified that melanoma patients exhibited a negative MIIP expression and predicted worse overall survival when compared with patients with a positive MIIP expression.…”

Section: Miip Regulates Pd-l1 Expression By Downregulating Hdac6supporting

confidence: 71%

MIIP downregulates PD-L1 expression through HDAC6 in malignant melanoma

Xing¹,

Li²,

Xiang³

et al. 2020

Preprint

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Background Immune checkpoint inhibitors have improved the objective response rate and survival of melanoma patients. However, there are still many melanoma patients suffering from disease progression due to primary or secondary immune checkpoint inhibitor resistance, as is observed in the failure of anti-PD1/PD-L1 therapy. It is urgent to determine the function of PD-1/PD-L1 expression in melanoma and its associated pathways to enhance the efficacy of anti-PD-1 therapies. Methods A cohort of 133 patients with histologically confirmed melanoma from Tianjin Medical University Cancer Institute & Hospital were included in this study. We performed immunohistochemical staining to detect the expression of MIIP, HDAC6 and PD-L1. Kaplan-Meier and log-rank test were used for survival analyze. As for vitro, Western blot was used to verify the signaling pathway that MIIP regulates PD-L1 expression. Results Our present data demonstrate MIIP expression was decreased in melanoma and that the negative expression of MIIP was correlated with worse overall survival. We also found the positive expression of HDAC6, a molecule that is downstream of MIIP, had a positive trend with decreased overall survival, because the p value was not statistically significant. At the same time, the positive expression of PD-L1, a crucial costimulatory molecule, was associated with decreased overall survival. Furthermore, there was a positive association between HDAC6 and PD-L1 protein expression (p<0.01). In vitro experiment, we found that increasing MIIP led to decreased HDAC6, pSTAT3, and PD-L1 expression. Knocking down MIIP led to increased HDAC6, pSTAT3, and PD-L1 expression. Combining the published results, showing that HDAC6 can regulate PD-L1 expression through STAT3, our present data suggest that MIIP inhibits the expression of PD-L1 by downregulating HDAC6 in melanoma. Most importantly, methods for targeting MIIP-HDAC6-PD-L1 pathways, such as treatment with HDAC6 inhibitors, might indicate a new therapeutic approach for enhancing immune checkpoint inhibitor therapies in melanoma. Conclusions Our findings highlight the immunomodulatory effects of MIIP in the inhibition of PD-L1 expression by downregulating HDAC6 in melanoma. Our data provide a sensible framework to consider the targeting of the MIIP-HDAC6-PD-L1 pathway.

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Section: Miip Regulates Pd-l1 Expression By Downregulating Hdac6supporting

confidence: 71%

MIIP downregulates PD-L1 expression through HDAC6 in malignant melanoma

Xing¹,

Li²,

Xiang³

et al. 2020

Preprint

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“…The migration and invasion inhibitory protein (MIIP), also known as IIp45, was first reported as a tumor suppressor gene in glioma 6. Previous studies showed that MIIP located in 1p36 chromosome where frequent deletion occurred, and it has low expression in various tumors, including glioma,6,7 non-small cell lung cancer (NSCLC),8 colorectal cancer,9 endometrial cancer,10 and breast cancer 11. Several potential mechanisms have been reported on how MIIP regulates cancers development and progression.…”

Section: Introductionmentioning

confidence: 99%

MIIP is downregulated in gastric cancer and its forced expression inhibits proliferation and invasion of gastric cancer cells in vitro and in vivo

Sun

Wang

Jiang

et al. 2018

OTT

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BackgroundMIIP is associated with cancer progression in various cancers. However, its expression pattern, and associated molecular mechanisms in gastric cancer (GC) progression are still mysterious. We aimed to explore the role of MIIP in proliferation and invasion of GC.Materials and methodsMIIP expression was evaluated in human GC tissues and cell lines. Public clinical database of GC patients was used to probe the correlation between MIIP expression and prognosis of patients. The effects of forced MIIP expression on GC cells were determined by MTT, cell cycle distribution, colony formation, wound-healing and Transwell assays in vitro, as well as in vivo growth of subcutaneous tumor xenografts and metastasis of xenografted tumors to the lungs in mice. The expressions of GC progression-associated genes, including HOTAIR, MALAT1, HDAC6, AC-tubulin, and cyclin D1, were assessed by Western blotting or qRT-PCR.ResultsBoth GC tissues and GC cell lines had lower MIIP expression. Higher level of MIIP in GC tissues predicts better survival in patients. Ectopic expression of MIIP in GC cell lines BGC823 and HGC27 induced G0/G1 cell cycle arrest and inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as the growth of GC xenografts and metastasis of tumors in vivo. Furthermore, overexpression of MIIP suppressed mRNA expressions of HOTAIR and MALAT1, decreased protein expression of HDAC6 and cyclin D1, and elevated AC-tubulin protein expression.ConclusionMIIP is a suppressor for GC progression and is a potential therapeutic target for treating GC.

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“… 66 AURKAIP1, FAAP20 67 , 68 MIIP MIIP, KIAA2013, SRM, PEX14, MAD2L2 1p36.22 Neither Neuroblastoma, breast cancer, etc. 66 MIIP, MAD2L2 69 , 70 CASP8AP2 CASP8AP2, SYNCRIP, MAP3K7, ZNF292, RNGTT 6q14.3 Ref. 18 CASP8AP2, MAP3K7 71 CCAR2 CCAR2, CHMP7, ELP3, CCDC25, INTS9 8p21.3 Ref.…”

Section: Resultsmentioning

confidence: 99%

“…Gene FAAP20 is needed in DNA repair pathway 68 . The deletion of gene MIIP can induce chromosomal instability 69 . Tumor suppressor gene MAD2L2 inhibits cancer growth 70 .…”

Section: Genomically Co-localized Signatures Associated With 1q213-qmentioning

confidence: 99%

Pan-cancer driver copy number alterations identified by joint expression/CNA data analysis

Wang

Anastassiou

2020

Sci Rep

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Analysis of large gene expression datasets from biopsies of cancer patients can identify co-expression signatures representing particular biomolecular events in cancer. Some of these signatures involve genomically co-localized genes resulting from the presence of copy number alterations (CNAs), for which analysis of the expression of the underlying genes provides valuable information about their combined role as oncogenes or tumor suppressor genes. Here we focus on the discovery and interpretation of such signatures that are present in multiple cancer types due to driver amplifications and deletions in particular regions of the genome after doing a comprehensive analysis combining both gene expression and CNA data from The Cancer Genome Atlas.

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MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer

Cited by 15 publications

References 43 publications

MIIP downregulates PD-L1 expression through HDAC6 in malignant melanoma

MIIP downregulates PD-L1 expression through HDAC6 in malignant melanoma

MIIP is downregulated in gastric cancer and its forced expression inhibits proliferation and invasion of gastric cancer cells in vitro and in vivo

Pan-cancer driver copy number alterations identified by joint expression/CNA data analysis

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