TMX2 potentiates cell viability of hepatocellular carcinoma by promoting autophagy and mitophagy.
Weiyu ZhangYao TangPengfei YangYutong ChenZhijie XuChunhui QiHongbin HuangRuiyang LiuHaorui QinHaoying KeCaini HuangFuyuan XuPengfei PangZhiju ZhaoHong ShanFei XiaoPublished in: Autophagy (2024)
The dysregulation of membrane protein expression has been implicated in tumorigenesis and progression, including hepatocellular carcinoma (HCC). In this study, we aimed to identify membrane proteins that modulate HCC viability. To achieve this, we performed a CRISPR activation screen targeting human genes encoding membrane-associated proteins, revealing TMX2 as a potential driver of HCC cell viability. Gain- and loss-of-function experiments demonstrated that TMX2 promoted growth and tumorigenesis of HCC. Clinically, TMX2 was an independent prognostic factor for HCC patients. It was significantly upregulated in HCC tissues and associated with poor prognosis of HCC patients. Mechanistically, TMX2 was demonstrated to promote macroautophagy/autophagy by facilitating KPNB1 nuclear export and TFEB nuclear import. In addition, TMX2 interacted with VDAC2 and VADC3, assisting in the recruitment of PRKN to defective mitochondria to promote cytoprotective mitophagy during oxidative stress. Most interestingly, HCC cells responded to oxidative stress by upregulating TMX2 expression and cell autophagy. Knockdown of TMX2 enhanced the anti-tumor effect of lenvatinib. In conclusion, our findings emphasize the pivotal role of TMX2 in driving the HCC cell viability by promoting both autophagy and mitophagy. These results suggest that TMX2 May serve as a prognostic marker and promising therapeutic target for HCC treatment. Abbreviation : CCCP: Carbonyl cyanide 3-chlorophenylhydrazone; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeat; ER: endoplasmic reticulum; HCC: hepatocellular carcinoma; KPNB1: karyopherin subunit beta 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; TFEB: transcription factor EB; TMX2: thioredoxin related transmembrane protein 2; VDAC2: voltage dependent anion channel 2; VDAC3: voltage dependent anion channel 3; WB: western blot.
Keyphrases
- oxidative stress
- poor prognosis
- prognostic factors
- cell death
- end stage renal disease
- endoplasmic reticulum
- reactive oxygen species
- induced apoptosis
- endoplasmic reticulum stress
- signaling pathway
- newly diagnosed
- dna damage
- chronic kidney disease
- transcription factor
- genome wide
- ejection fraction
- long non coding rna
- peritoneal dialysis
- binding protein
- gene expression
- stem cells
- endothelial cells
- mesenchymal stem cells
- bone marrow
- cell cycle arrest
- high throughput
- cancer therapy
- cell proliferation
- dna methylation
- estrogen receptor
- human health
- pi k akt