Table 1.

A non-exhaustive list of studies showing tumor suppressor or pro-tumorigenic activities of CD9 in cancer.

Impact on cancer	Cancer type	Potential mechanism	References
Tumor suppressor activity	Prostate carcinoma	• CD9 downregulation during prostate cancer progression often due to deletions or mutations in its transcript• CD9 expression increased upon androgen therapy• Ablation of CD9 had no detectable effect on de novo primary tumor onset, but increased liver metastases• Inverse relationship of CD9 with CD151 in EVs; CD9low and CD151high EV populations have increased TGF-β-induced protein and several subunits of the proteasome complex	127–129,145
	Lung carcinoma (NSCLC)	• Inhibition of cell motility and invasiveness	131,132
	Lung carcinoma (SCLC)	• Absence of CD9 contributed to differentiation and MMP-2 production via PI3K/Akt pathway, while ectopic expression of CD9 suppressed neurite-like process outgrowth and promoted apoptotic death• Reduction in cell motility through association with β1 integrin	130,133
	Colon carcinoma	• Ectopic expression of CD9 enhanced β1 integrin-dependent adhesion and inhibition of cell growth	134,135
	Breast carcinoma	• CD9 suppression resulted in increased motility • CD9 suppression resulted in decreased spread and increased motility, attributed to specific CD9-mediated control of the localization of talin, a critical regulator of integrin activation, to focal adhesion	136–141
	Mesothelioma	• CD9: favorable prognostic marker for inhibition of cell migration• CD9 and CD26 co-modulated with each other. Depletion of CD26 led to an increase in CD9 and vice versa. CD9 depletion led to enhanced invasiveness. CD9 negatively regulated tumor cell invasion by reducing the level of CD26-α5β1 integrin complex	143,144
	Gastric carcinoma	• In metastatic gastric cancer tissues, LSD1 deletion suppressed gastric cancer migration by decreasing intracellular miR-142-5p, which led to the upregulation of CD9	205
	Hepatocellular carcinoma	• The upregulation of CD9 suppressed carcinoma development via c-Jun N-terminal kinase (JNK) signaling pathway	206
	Fibrosarcoma	• Through its association with EWI-2/EWI-F/β1 complex and EGFR pathway, and the activation of Akt and p38 signaling, CD9 promoted cell apoptosis and cell spreading, and inhibited cell adhesion, migration, and cell colony formation	207
	Cervical carcinoma	• Strong local expression of CD9 at sites of trans-endothelial invasion is associated with progression of cervical carcinomas	208
Pro-tumorigenic and metastatic activities	Lung carcinoma (NSCLC)	• CD9 increased cell migration to chemoattractants including IL-16• CD9 is a factor of poor prognosis	8,209
	Ovarian carcinoma	• CD9 overexpression induced TNF-α, IL-6, and IL-8 and activation of the NF-κB signaling pathway• CD9 overexpressed in primary ovarian tumors versus normal human ovarian surface epithelium	150–152
	Breast carcinoma	• CD9 expression associated with worse overall and disease-free survival in patients with invasive lobular carcinoma• CD9 overexpression promoted the development of bone metastases• CD9 on stromal immune cells was associated with a longer disease-free survival, while CD9 on tumor cells correlated with both lymph node and distant metastases• In breast cancer cell lines, CD9 sequestered and destabilized claudin-1, preventing its association with the tight junctions and resulting in increased epithelial-mesenchymal transition and migration and thus promoting tumor progression• Silencing CD9 in MDA-MB-231 cells affected the proper formation of plasma membrane protrusions, and reduced cell migration• CD9/CD81-silenced cells showed delayed α3β1-dependent cell spreading and impaired directed motility and altered front-rear cell morphology, linked to breast carcinoma progression and metastasis	62,122,148,149,155,210
	Gastric carcinoma	• CD9 expression was greater in tissues from primary and metastatic gastric carcinoma than in surrounding stroma and higher expression of CD9 correlated with vessel invasion, lymph node metastasis, and advanced stage• CD9 positivity correlated with the highly malignant scirrhous-type, with lymph node metastasis and venous invasion. • CD9-positive EVs from cancer-associated fibroblasts stimulated the migration and invasion of cancer cells	146,147
	Pancreatic carcinoma	• CD9 identified a subpopulation of pancreatic cancer stem cells capable of initiating the carcinoma and give rise to its heterogeneity. CD9 modulated glutamine metabolism to fuel tumor growth	211
	Multiple myeloma	• CD9 expression was upregulated in vivo by the close interaction of myeloma cells with bone marrow endothelial cells, resulting in trans-endothelial invasion	212

NSCLC: non-small cell lung cancer; SCLC: small-cell lung cancer.