2. Academic Validation
  3. Knockdown of membrane-bound complement regulatory proteins suppresses colon cancer growth in mice through inducing tumor cell apoptosis

Knockdown of membrane-bound complement regulatory proteins suppresses colon cancer growth in mice through inducing tumor cell apoptosis

  • Int Immunopharmacol. 2022 Nov 26;114:109450. doi: 10.1016/j.intimp.2022.109450.
Guanghua Tang 1,  Linyue Pan 2,  Zhixiang Wang 1,  Hua Zhu 1,  Yong Yang 1,  Zijian Wang 1,  Hongqin Yue 1,  Yuhua Shi 1,  Dichen Wu 1,  Zhilong Jiang 3,  Danbin Jiang 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Yancheng Third People's Hospital, The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng 224005, China.
  • 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 4 Department of Gastroenterology, Yancheng Third People's Hospital, The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng 224005, China. Electronic address: [email protected].
PMID: 36446233 DOI: 10.1016/j.intimp.2022.109450
Abstract

CD46, CD55 and CD59 are membrane-bound Complement Regulatory Proteins (mCRPs) and highly expressed in many tumor tissues. Our analysis by RNA sequencing and qRT-PCR revealed that the expression of mCRPs was significantly elevated in Cancer tissues of 15 patients with colon Cancer. To further investigate the role of mCRPs in the development of colon Cancer, we suppressed the expression of mCRPs by CD46-shRNA, CD55-shRNA and CD59-shRNA in colon Cancer cell lines, SW620 and HT-29 cells. The results indicated that CD46-shRNA, CD55-shRNA and CD59-shRNA effectively reduced the expression of mCRPs, accompanied with the increased LDH release and the percentage of Annexin V + 7-AAD- early phase of apoptotic cells. The similar cytotoxic effects were also observed in the cells treated with CD46 neutralizing antibody (aCD46), associated with the increased C5b-9 deposition, cleaved Caspase-3 and Bax expression in the treated cells. The cytotoxic effects by mCRPs knock-down were potentiated in the cells co-treated with doxorubicin (Dox). In addition, STAT3, STAT6, and p38 MAPK inhibitors, including C188-9, AS1517499 and SB203580 effectively reduced the expression of CD46 in the treated colon cells, associated with increased cell Apoptosis and LDH release. Further study with mouse model revealed that mCRPs knockdown by mCRPs-shRNA significantly reduced colon Cancer growth, associated with increased expression of Bax, cleaved Caspase-3 and C5b-9 deposition, but reduced expression of Bcl-2, IL-6 and IL-1beta in tumor tissues of nude mice transplanted with SW620 cells. Thereby, mCRPs expression in human colon Cancer cells were upregulated by STAT3/STAT6/p38 MAPK signaling and mCRPs knockdown reduced colon Cancer growth in mice through inducing tumor cell Apoptosis.

Keywords

Apoptosis; Colon cancer; Complement; Membrane-bound complement regulatory proteins (mCRPs).

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