“Rogue” Protein Could Contribute to Humans’ High Cancer Rates

ABOVE: A tissue section from a prostate cancer patient who produces Siglec-XII (stained brown), which is much more highly expressed in malignant cells than normal cells. 
FASEB BIOADVANCES, DOI:10.1096/FBA.2020-00092, 2020

EDITOR’S CHOICE IN CANCER BIOLOGY

The paper
S.S. Siddiqui et al., “Human-specific polymorphic pseudogenization of SIGLEC12 protects against advanced cancer progression,” FASEB BioAdvances, 3:69–82, 2021.

Among a group of cell surface proteins known as sialic-acid-binding immunoglobulin-like lectins (Siglecs), CD33-related Siglecs are found mainly on innate immune cells and are involved in cell signaling. One Siglec, however, appears to have “gone rogue” in humans, according to Ajit and Nissi Varki, a husband-and-wife team at the UC San Diego School of Medicine. 

Siglec-XII, encoded by the gene SIGLEC12, no longer binds sialic acid and seems to be involved in abnormal cell signaling in humans, the researchers report. The Varkis argue that the protein plays a role in cancer progression and could help explain why humans have much higher rates of carcinoma—cancers that arise from epithelial cells, where Siglec-XII is abundant—than do other great apes. 

Only about 30 percent of humans produce this rogue protein; most people have a mutation that inactivates SIGLEC12. The Varkis and their colleagues found Siglec-XII in about 80 percent of carcinoma samples but in just 35 percent of normal tissues. When they forced production of Siglec-XII in a human prostate cancer cell line, the result was higher expression of cancer progression–related genes than in prostate cancer cells that lacked the protein. And comparing cohorts of cancer patients, the team found that functional SIGLEC12 was associated with poor prognosis in late-stage colorectal cancer patients. 

“The study proposes very interesting hypotheses,” says Jun Wang, an immunologist at NYU Langone Health who was not involved in the research. But, he says, more evidence is needed to confirm Siglec-XII’s role in cancer progression because artificial overexpression of the protein in prostate cancer cells could differ from how the protein behaves in tumors. He notes that it would also be interesting to examine how Siglec-XII in immune cells contributes to cancer. “The cancer cell is just part of the puzzle. The whole picture is cancer and the immune system.”