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PHLPP1 过表达与胃癌中 AKT 活性降低相关，提示预后良好。

PHLPP1 Overexpression was Associated With a Good Prognosis With Decreased AKT Activity in Gastric Cancer.

机构信息

26720Gyeongsang National University, Jinju, South Korea.

553954Gyeongsang National University Changwon Hospital, Changwon, South Korea.

出版信息

Technol Cancer Res Treat. 2022 Jan-Dec;21:15330338211067063. doi: 10.1177/15330338211067063.

DOI:10.1177/15330338211067063
PMID:34982011
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8733352/
Abstract

The aim of this study was to perform a clinicopathologic analysis of PHLPP1 expression in gastric cancer patients and analyze AKT activity with chemotherapy drug treatment in cancer subtypes. Surgically resected gastric cancer tissue specimens were obtained from 309 patients who underwent gastrectomy, and PHLPP1 expression was validated by tissue microarray analysis with immunohistochemistry. We assessed whether PHLPP1 selectively dephosphorylates Ser473 of AKT in an in-vitro study. We found that the PHLPP1 overexpression (OE) group showed significantly greater proportions of differentiated subtype samples and early T stage samples, lower lymph node metastasis, and lower TNM stage than the PHLPP1 underexpression (UE) group. The overall survival of the PHLPP1-OE group was significantly higher (53.39 ± 0.96 months) than that of the PHLPP1-UE group (47.82 ± 2.57 months) ( = .01). In vitro analysis, we found that the PHLPP1-OE group showed a significant decrease in relative AKT S-473 levels in both cell lines (MKN-74 and KATO-III). We found that treatment with chemotherapy drugs decreased the activity of Ser473 in the MKN-74 cell line with PHLPP1 OE, but it did not affect the activity of Ser473 in KATO-III cells. We found that patients who overexpressed PHLPP1 showed low recurrence and good prognosis. PHLPP1 was found to work by lowering the activity of AKT Ser473 in gastric cancer. Additionally, we found a clue regarding the mechanism of chemotherapeutic drug resistance in a cell line of signet ring cell origin and will uncover this mechanism in the future.

摘要

本研究旨在对胃癌患者的 PHLPP1 表达进行临床病理分析，并分析癌症亚型中 AKT 活性与化疗药物治疗的关系。通过免疫组织化学组织微阵列分析，从 309 例接受胃切除术的胃癌患者中获得了手术切除的胃癌组织标本，并验证了 PHLPP1 的表达。我们评估了 PHLPP1 是否在体外研究中选择性地使 AKT 的 Ser473 去磷酸化。我们发现，与 PHLPP1 低表达（UE）组相比，PHLPP1 过表达（OE）组具有更高比例的分化型亚型样本和早期 T 期样本、更低的淋巴结转移和更低的 TNM 分期。PHLPP1-OE 组的总生存率（53.39 ± 0.96 个月）显著高于 PHLPP1-UE 组（47.82 ± 2.57 个月）（ = .01）。体外分析发现，在两种细胞系（MKN-74 和 KATO-III）中，PHLPP1-OE 组的相对 AKT S-473 水平显著降低。我们发现，用化疗药物治疗可降低 PHLPP1 OE 的 MKN-74 细胞系中 Ser473 的活性，但不影响 KATO-III 细胞中 Ser473 的活性。我们发现，PHLPP1 过表达的患者复发率低，预后良好。PHLPP1 通过降低胃癌中 AKT Ser473 的活性起作用。此外，我们在一种印戒细胞来源的细胞系中发现了化疗药物耐药机制的线索，并将在未来揭示这一机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/603006ad4e97/10.1177_15330338211067063-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/6ea54103f382/10.1177_15330338211067063-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/ef4cdfcbc402/10.1177_15330338211067063-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/be4e5fe75601/10.1177_15330338211067063-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/603006ad4e97/10.1177_15330338211067063-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/6ea54103f382/10.1177_15330338211067063-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/ef4cdfcbc402/10.1177_15330338211067063-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/be4e5fe75601/10.1177_15330338211067063-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eec1/8733352/603006ad4e97/10.1177_15330338211067063-fig4.jpg

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