An increasing number of experiments have been conducted around the four-transmembrane protein family and cancer; further, exploring the molecular mechanism of tumor growth and invasiveness has become the key to the development of new therapies[14–16]. However, previous studies have mostly focused on the mechanism of individual members of the TSPAN family in independent cancer types[17–19]. Therefore, a systematic analysis of the TSPAN family helps us to clarify its role in the development of tumors and guide the search for new tumor markers. To achieve this goal, we analyzed the expression of 33 TSPAN family proteins in 21 common tumors through the public database Oncomine, and we focused on their role in 3 common digestive tract tumors.
TSPAN15 is believed to enhance tumor stemness, and it has the ability to promote tumor growth and recurrence[20]. TSPAN12 can promote tumor cell proliferation and colony formation, and high expression of CD9 is considered to be related to lymph node metastasis[21, 22]. In contrast, another portion of the four-transmembrane protein family showed tumor suppression. For example, TSPAN13 has been shown to be a tumor suppressor gene in breast cancer, while TSPAN1 can inhibit the migration of alveolar epithelial cells and the EMT process[23, 24]. At the same time, other studies have found that the TSPAN proteins can regulate the phosphorylation and homodimerization of key proteins that affect the drug resistance of tumors[2]. Therefore, we believe that as a key transmembrane protein family on the cell membrane, the TSPAN protein plays a pivotal role in tumorigenesis and development. This article analyzed the expression differences of TSPAN family members in human cancer and normal tissues through an online database and explored TSPAN proteins as potential prognostic biomarkers in cancer. According to the analysis of the Oncomine public database, we found that TSPAN5 is highly expressed in liver cancer and colon cancer, TSPAN26 is highly expressed in liver cancer and gastric cancer, and TSPAN9, TSPAN28, and TSPAN29 are highly expressed in gastric and colon cancer. Interestingly, we also found that TSPAN7 was consistently underexpressed in all three digestive tract tumors. Therefore, TSPAN7 has attracted our interest for further research.
In clear cell renal cell carcinoma, the higher the TSPAN7 gene expression, the smaller the number of TSPAN7-positive blood vessels, and the less infiltration and metastasis of the cells, suggesting that TSPAN7 may act as a tumor growth inhibitor and affect tumor progression and metastasis[25]. There are reports in the literature that TSPAN 7 is upregulated in lung cancer cells, and its high expression is closely related to the poor prognosis of lung cancer patients, suggesting that TSPAN 7 plays an oncogenic role in lung cancer[26, 27]. However, the role of TSPAN7 in tumors of the digestive system has not been confirmed. We found through biochemical analysis that the expression of TSPAN7 was downregulated in gastric cancer, liver cancer and intestinal cancer, suggesting that TSPAN7 may play opposite roles in lung cancer and lung cancer. Through real-time PCR and Western blot experiments, we found that compared with normal cells, the expression of TSPAN7 in liver cancer cells was significantly reduced, while its expression in gastric and colon cancer was not significantly different from normal cells. Considering that the pathological types of gastric cancer and colorectal cancer are both adenocarcinoma, while liver cancer is cell carcinoma, the expression of TSPAN7 may be different depending on the tumor site and tissue pathology.
In subsequent studies, we mainly studied the role of Tspan7 in liver cancer cells. Since the four-transmembrane protein family also directly or indirectly participates in the process of cell proliferation, invasion and metastasis, we hope to understand what role Tspan7 plays in liver cancer cells[9, 28–30]. The results showed that the high expression of Tspan7 not only inhibited the proliferation of HCC-LM3 cells but also inhibited the invasion and metastasis of liver cancer cells. Animal experiments have also confirmed that TSPAN7 has a tumor suppressive effect in vivo. Therefore, we believe that TSPAN7 plays a tumor suppressive role in liver cancer cells. However, the downstream signaling pathways that regulate these biological functions in tumor cells and their underlying molecular mechanisms need further study.