Phospholipid Phosphatase 4 promotes proliferation and tumorigenesis, and activates Ca2+-permeable Cationic Channel in lung carcinoma cells

Mol Cancer. 2017 Aug 29;16(1):147. doi: 10.1186/s12943-017-0717-5.

Xin Zhang ¹ ² ³, Lan Zhang ⁴, Bihua Lin ³, Xingxing Chai ⁵, Ronggang Li ², Yuehua Liao ², Xinghui Deng ², Qiongru Liu ², Wenli Yang ², Yubo Cai ², Wei Zhou ², Zhichao Lin ⁶, Wenhai Huang ⁶, Meigong Zhong ⁷, Fangyong Lei ⁸, Jinhua Wu ⁹, Shuaishuai Yu ⁹, Xiaoping Li ¹⁰, Shangren Li ¹⁰, Yueyue Li ¹¹, Jincheng Zeng ³, Wansheng Long ¹¹, Dong Ren ¹² ¹³, Yanming Huang ¹⁴ ¹⁵

Affiliations

1 Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
2 Department of Pathology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
3 Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, 523808, China.
4 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
5 Laboratory Animal Center, Guangdong Medical University, Zhanjiang, 524023, China.
6 Department of Thoracic Surgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
7 Department of Pharmacy, Jiangmen Maternity and Child Health Care Hospital, Jiangmen, 529030, China.
8 Department of Oncology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
9 Department of Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
10 Department of General Surgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
11 Department of Radiology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China.
12 Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, 523808, China. summeryang818ren@outlook.com.
13 Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan 2rd Road, Guangzhou, Guangdong Province, 510080, China. summeryang818ren@outlook.com.
14 Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China. huangyanming_jxy@163.com.
15 Department of Respiration Medicine, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China. huangyanming_jxy@163.com.

PMID: 28851360 DOI: 10.1186/s12943-017-0717-5

Abstract

Background: Phospholipid Phosphatase 4 (PPAPDC1A or PLPP4) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to investigate the clinical significance and biological roles of PLPP4 in lung carcinoma.

Methods: PLPP4 expression was examined in 8 paired lung carcinoma tissues by Real-Time PCR and in 265 lung carcinoma tissues by immunohistochemistry (IHC). Statistical analysis was performed to evaluate the clinical correlation between PLPP4 expression and clinicopathological features and survival in lung carcinoma patients. In vitro and in vivo assays were performed to assess the biological roles of PLPP4 in lung carcinoma. Fluorescence-activated cell sorting, Western blotting and luciferase assays were used to identify the underlying pathway through which PLPP4 silencing mediates biological roles in lung carcinoma.

Results: PLPP4 is differentially elevated in lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SQC) tissues. Statistical analysis demonstrated that high expression of PLPP4 significantly and positively correlated with clinicopathological features, including pathological grade, T category and stage, and poor overall and progression-free survival in lung carcinoma patients. Silencing PLPP4 inhibits proliferation and cell cycle progression in vitro and tumorigenesis in vivo in lung carcinoma cells. Our results further reveal that PLPP4 silencing inhibits CA²⁺-permeable cationic channel, suggesting that downregulation of PLPP4 inhibits proliferation and tumorigenesis in lung carcinoma cells via reducing the influx of intracellular CA²⁺.

Conclusion: Our results indicate that PLPP4 may hold promise as a novel marker for the diagnosis of lung carcinoma and as a potential therapeutic target to facilitate the development of novel treatment for lung carcinoma.

Keywords

Ca2+-permeable cationic channel; Cell cycle; Lung carcinoma; PLPP4; Proliferation; Therapeutic target; Tumorigenesis.

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